CN1857220B - Slow released antituberculotic preparation - Google Patents
Slow released antituberculotic preparation Download PDFInfo
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- CN1857220B CN1857220B CN2006102003156A CN200610200315A CN1857220B CN 1857220 B CN1857220 B CN 1857220B CN 2006102003156 A CN2006102003156 A CN 2006102003156A CN 200610200315 A CN200610200315 A CN 200610200315A CN 1857220 B CN1857220 B CN 1857220B
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Abstract
The slow released antituberculotic preparation is implanting agent or injection with slow releasing of medicine in the local tuberculosis focus to maintain 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 consists of slow releasing supplementary material and antituberculotic selected from rifampicin, rifamycin, rifapentine and/or rifabutine. The solvent is special solvent containing suspending agent of 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 preparation may be prepared with slow released microsphere. The present invention has obvious and unique treating effect on various kinds of intractable tuberculosis.
Description
(1) technical field
The present invention relates to a kind of slow released antituberculotic preparation, belong to technical field of pharmaceuticals.Particularly, the invention provides a kind of slow releasing agent that contains antituberculotics, be mainly slow releasing injection and sustained-release implant.This slow releasing agent topical application is main, can and keep active drug concentration in the local acquisition of tuberculose focus.
(2) background technology
The tuberculosis that with the pulmonary tuberculosis is representative was exactly a kind of disease that has a strong impact on people ' s health originally, was widely current in the whole world, had seized several hundred million people's life, and people are referred to as white pestilence, and saying of " ten consumptive diseases nine being dead " once arranged.Along with the appearance of antituberculosis drugses such as streptomycin, tuberculosis has become a kind of medicable disease.Yet along with people to the ignorance of its seriousness, it is relevant that to prevent and treat the obvious deficiency, the treatment that drop into the aspect lack of standardization, the drug-fast generation of the tulase that causes has thus become successfully treats this sick most thorny issue.
Because its infectiousness is very strong, the annual in recent years whole world of its sickness rate is increasing with 1% speed.Need in three kinds of diseases of emphasis control in the whole world that World Health Organization (WHO) determines, tuberculosis is only second to acquired immune deficiency syndrome (AIDS), occupies before the malaria.The whole world promptly has a people to be subjected to tubercle bacillus affection the each second, and per minute has 3 to 4 people because of tuberculosis death, and the whole world 3,000,000 people that still have an appointment every year on average die from tuberculosis at present.The tuberculosis of China is at present popular very serious, has now become one of 22 the high burden of tuberculosis countries in the world; China has 6,000,000 tuberculosis patients approximately at present, accounts for 1/3rd of global number of patients, occupies the second place of the world and is only second to India; Accounted for 1/4th of the whole world Chinese drug resistance patient.The whole nation has at least 1,500,000 routine new patients take place every year, and wherein the infectiousness patient surpasses 650,000 examples, and annual number because of tuberculosis death is up to 250,000, and mostly is young and middle-aged.It has become No.1 killer as single infectious disease.Tuberculosis needs the continuous use more than six months just can obtain satisfied prognosis.Because treatment time is longer, many patients may just forget in time quantitatively to take medicine, thereby often cause chemical sproof generation.And drug-resistant tuberculosis people's treatment is spinning out of time on the one hand, is exactly multiple medication combined chemotherapy application charges costliness on the other hand.As needing more than 10,000 yuan in China.Therefore, research and develop the world subject that new effectively preventing preparation lungy or method have become eager solution.
At present, there are many new antituberculotics to demonstrate curative effect preferably, however not ideal enough to anti-multiple medicines tuberculosis (MDR-TB) effect.Because to a lot of chronic lesions, particularly local lesion, the routine treatment administration is difficult to obtain effective bacteriocidal concentration.Escalated dose or take medicine for a long time as having a lot of side effect.
(3) summary of the invention
The present invention is directed to the deficiencies in the prior art, a kind of slow releasing agent that contains anti-tuberculosis drugs is provided, particularly, is a kind of slow released antituberculotic preparation that contains rifampicin, is mainly slow releasing injection and sustained-release implant.
Rifampicin is mainly oral formulations abroad as a kind of anti-tuberculosis drugs commonly used, even general injection is also not ideal enough, because can not obtain active drug concentration in lesions position.And significantly general toxicity and drug-fast generation have greatly limited the application of this medicine in application process.
The present invention finds, anti-tuberculosis drugs is made slow releasing agent (being mainly slow releasing injection and sustained-release implant) not only can greatly improve partial drug level, reduce the concentration of medicine in blood circulation, reduce the toxicity of medicine normal structure, can also greatly make things convenient for medicinal application, reduce the course of treatment, shorten treatment time, reduce medicine complication, reduce patient expense, reduce drug resistance.The above unexpected main contents of the present invention of finding to constitute.
A kind of form of medicinal slow release agent of the present invention is a slow releasing injection, is made up of sustained-release micro-spheres and solvent.Particularly, this slow releasing injection is grouped into by following one-tenth:
(a) sustained-release microparticle, the one-tenth following by percentage by weight is grouped into:
Anti-tuberculosis drugs 1-70%
Slow-release auxiliary material 30-99%
Suspending agent 0.0-30%
More than be weight percentage
With
(b) solvent is for common solvent or contain the special solvent of suspending agent.
Wherein,
Anti-tuberculosis drugs is selected from rifampicin and analog thereof; Slow-release auxiliary material is selected from one of copolymer (PLGA), xylitol, oligosaccharide, chrondroitin, chitin, hyaluronic acid, collagen protein, gelatin and white tempera of polifeprosan, bis-fatty acid and decanedioic acid copolymer (PFAD-SA), poly-(erucic acid dimer-decanedioic acid) [P (EAD-SA)], poly-(fumaric acid-decanedioic acid) [P (FA-SA)], ethylene vinyl acetate copolymer (EVAc), polylactic acid (PLA), polyglycolic acid and hydroxyacetic acid or its combination; Suspending agent is selected from one of sodium carboxymethyl cellulose, (iodine) glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, soil temperature 20, soil temperature 40 and soil temperature 80 or its combination.
The analog of rifampicin (rifampin) comprise rifamycin (rifamycin), rifapentine (rifapentine, DL473, rifapentine), utilize the cloth spit of fland (the sharp good fortune of spirocyclic piperidine is mould, ansamycin, LM427).Optional a kind of in rifampicin and analog thereof of anti-tuberculosis drugs of the present invention or several.
Above-mentioned anti-tuberculosis drugs shared ratio in compositions is decided because of concrete condition, can be 1%-70%, is good with 2%-50%, and 5%-40% is best.
The effective ingredient in the tuberculosis sustained-release micro-spheres of the present invention and the percentage by weight of slow-release auxiliary material are preferably as follows:
Anti-tuberculosis drugs 2-50%
Slow-release auxiliary material 50-98%
Suspending agent 0.0-30%
Slow-release auxiliary material is selected from copolymer, hyaluronic acid, collagen protein or the gelatin of polifeprosan, bis-fatty acid and decanedioic acid copolymer (PFAD-SA), poly-(erucic acid dimer-decanedioic acid), poly-(fumaric acid-decanedioic acid), ethylene vinyl acetate copolymer, polylactic acid, polyglycolic acid and hydroxyacetic acid.
Effective ingredient in the sustained-release micro-spheres of the present invention and percentage by weight are most preferably as follows:
(a) rifampicin of 5-40%, rifamycin, rifapentine or utilize the cloth spit of fland;
(b) rifamycin of the rifampicin of 5-40% and 5-40%, rifapentine or utilize the combination in cloth spit of fland;
(c) rifapentine of the rifamycin of 5-40% and 5-40% or utilize the combination in cloth spit of fland: or
(d) combination that utilizes the cloth spit of fland of the rifapentine of 5-40% and 5-40%.
The percentage by weight of slow-release auxiliary material is most preferably as follows in the sustained-release micro-spheres of the present invention:
(1) PLA of 55-90%;
(2) PLGA of 50-90%;
(3) polifeprosan of 50-85%;
(4) bis-fatty acid of 55-90% and decanedioic acid copolymer; Or
(5) EVAc of 55-90%.
Above sustained-release micro-spheres is made slow releasing injection with the solvent of the suspending agent that contains sodium carboxymethyl cellulose, (iodine) glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, soil temperature 20, soil temperature 40 or soil temperature 80.Wherein the concentration of sodium carboxymethyl cellulose in solvent can be 0.1-5%, but serves as preferred with 0.5 3%, with 1-2% for most preferably.
The molecular weight peak value of polylactic acid can be, but is not limited to, 5000-100, and 000, but with 20,000-60,000 is preferred, with 30,000-50,000 for most preferably; The molecular weight of polyglycolic acid can be, but is not limited to, 5000-100, and 000, but with 20,000-60,000 is preferred, with 30,000-50,000 for most preferably; Above polyhydroxy acid can singly select or multiselect.When singly selecting, serve as preferred with the copolymer (PLGA) of polylactic acid (PLA) or hydroxy carboxylic acid and glycolic, the molecular weight of copolymer can be, but is not limited to, 5000-100,000, but with 20,000-60,000 be preferably, with 30,000-50,000 for most preferably; When multiselect, compound polymer or the copolymer formed with macromolecule polymer or different macromolecule polymer serve as preferred, with the compound polymer that contains different molecular weight polylactic acid or decanedioic acid or copolymer for most preferably, as, but be not limited to, molecular weight is 1000 to 30000 polylactic acid with molecular weight is that 20000 to 50000 polylactic acid mixes, molecular weight is 10000 to 30000 polylactic acid with molecular weight is that 30000 to 80000 PLGA mixes, molecular weight is that 20000 to 30000 polylactic acid mixes with decanedioic acid, molecular weight is that 30000 to 80000 PLGA mixes with decanedioic acid.
In various high molecular polymers, with polylactic acid, decanedioic acid, the mixture or the copolymer that contain the macromolecule polymer of polylactic acid or certain herbaceous plants with big flowers diacid is first-selection, mixture and copolymer can be selected from, but be not limited to the mixture or the copolymer of the mixture of PLA, PLGA, glycolic and hydroxy carboxylic acid, certain herbaceous plants with big flowers diacid and fragrant polyanhydride or aliphatic polyanhydride.The blend ratio of glycolic and hydroxy carboxylic acid is 10/90-90/10 (weight), preferably 25/75-75/25 (weight).The method of blend is arbitrarily.Content when glycolic and hydroxy carboxylic acid copolymerization is respectively percentage by weight 10-90% and 90-10%.The representative of fragrance polyanhydride is polifeprosan [poly-(1,3-two (to the carboxyl phenoxy group) propane-decanedioic acid) (p (CPP-SA)), bis-fatty acid-decanedioic acid copolymer (PFAD-SA)], poly-(erucic acid dimer-decanedioic acid) [P (EAD-SA)] and poly-(fumaric acid-decanedioic acid) [P (FA-SA)] etc.Content during to carboxylic phenoxypropane (p-CPP) and decanedioic acid copolymerization is respectively percentage by weight 10-60% and 20-90%, and the blend weight ratio is 10-40: 50-90, preferably weight ratio 15-30: 65-85.
Except that above-mentioned adjuvant, also can select for use other materials to see the United States Patent (USP) (patent No. 4757128; 4857311; 4888176; 4789724) and in " pharmaceutic adjuvant complete works " (the 123rd page, Sichuan science tech publishing house published in 1993, Luo Mingsheng and Gao Tianhui chief editor) have a detailed description.In addition, Chinese patent (application number 96115937.5; 91109723.6; 9710703.3; 01803562.0) and U.S.'s patent of invention (patent No. 5,651,986) also enumerated some pharmaceutic adjuvant, comprise filler, solubilizing agent, absorption enhancer, film former, gellant, system (or causing) hole agent, excipient or blocker etc.
For regulating drug releasing rate or changing other characteristic of the present invention, can change the composition and the proportioning of monomer component or molecular weight, interpolation or the adjusting pharmaceutic adjuvant of polymer, add the water-soluble low-molecular chemical compound, as, but be not limited to various sugar or salt etc.Wherein sugar can be, but is not limited to, xylitol, oligosaccharide, (sulphuric acid) chrondroitin and chitin etc., and wherein salt can be, but is not limited to, potassium salt and sodium salt etc.
In the slow releasing injection, drug sustained release system can be made into microsphere, sub-micro ball, microemulsion, nanosphere, granule or spherical piller, makes the injection use then with after the injection solvent mixes.In various slow releasing injection, serve as preferred with the suspension type slow releasing injection, the suspension type slow releasing injection is the preparation that the drug sustained release system that will contain the tuberculosis composition is suspended in gained in the injection, used adjuvant is a kind of or its combination in the above-mentioned slow-release auxiliary material, and used solvent is common solvent or the special solvent that contains suspending agent.Common solvent is, but is not limited to the buffer that distilled water, water for injection, physiology are prepared towards liquid, dehydrated alcohol or various salt.The purpose of suspending agent is the pastille microsphere that effectively suspends, thereby is beneficial to the usefulness of injection.
Suspending agent is selected from one of sodium carboxymethyl cellulose, (iodine) glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, soil temperature 20, soil temperature 40 and soil temperature 80 or its combination.
The content of suspending agent in common solvent is decided because of its characteristic, can be 0.1-30% and decides because of concrete condition.Consisting of of preferred suspending agent:
A) 0.5-5% sodium carboxymethyl cellulose+0.1-0.5% soil temperature 80; Or
B) 5-20% mannitol+0.1-0.5% soil temperature 80; Or.
C) 0.5-5% sodium carboxymethyl cellulose+5-20% sorbitol+0.1-0.5% soil temperature 80.
The preparation method of slow releasing injection is arbitrarily, available some kinds of methods preparation: as, but be not limited to, mixing method, fusion method, dissolution method, spray drying method for preparation microsphere, dissolution method are made micropowder, liposome bag medicine method and emulsion process etc. in conjunction with freezing (drying) comminuting method.Serve as preferred wherein with dissolution method (being the solvent volatility process), seasoning, spray drying method and emulsion process.Microsphere then can be used for preparing above-mentioned various slow releasing injection, and its method is arbitrarily.The particle size range of used microsphere can be between 5-400um, serving as preferred between the 10-300um, with between the 20-200um for most preferably.
Microsphere also can be used for preparing other slow releasing injection, as gel injection, gel rubber sustained-release injection, block copolymer micelle injection.Wherein, block copolymer micelle is formed in aqueous solution by hydrophobic-hydrophilic block copolymers, has spherical inner core-shell mechanism, and hydrophobic block forms kernel, and hydrophilic block forms shell.The carrier micelle injection enters the purpose that reaches control drug release or targeted therapy in the body.Used pharmaceutical carrier is above-mentioned any one or its combination.Wherein preferred molecular weight is the hydrophilic block of the Polyethylene Glycol (PEG) of 1000-15000 as the micelle copolymer, and preferred biological degradation polyalcohol (as PLA, polylactide, polycaprolactone and copolymer thereof (molecular weight 1500-25000)) is as the hydrophobic block of micelle copolymer.The particle size range of block copolymer micelle can be between 10-300um, between the 20-200um serving as preferred.Gel injection system is dissolved in some amphipathic solvent with biological degradation polyalcohol (as PLA, PLGA or DL-LA and epsilon-caprolactone copolymer), adds medicine miscible with it (or suspendible) back again and forms flowability gel preferably, can be through local injection.In case inject, amphipathic solvent diffuses to body fluid very soon, the moisture in the body fluid then infiltrates gel, makes polymer cure, slowly discharges medicine.
The present invention finds to influence medicine and/or sustained-release micro-spheres suspends and/or the key factor of injection is the viscosity of solvent, and viscosity is big more, and suspension effect is good more, and syringeability is strong more.This unexpected one of main index characteristic of the present invention of finding to have constituted.The viscosity of solvent depends on the viscosity of suspending agent, and the viscosity of suspending agent is 100cp-3000cp (20 ℃-30 ℃ time), preferred 1000cp-3000cp (20 ℃-30 ℃ time), most preferably 1500cp-3000cp (20 ℃-30 ℃ time).According to the viscosity of the prepared solvent of this condition is 10cp-650cp (20 ℃-30 ℃ time), preferred 20cp-650cp (20 ℃-30 ℃ time), most preferably 60cp-650cp (20 ℃-30 ℃ time).
The preparation of injection has several different methods, and a kind of is that the sustained-release microparticle (A) of suspending agent for " 0 " directly mixed in special solvent, obtains corresponding sustained-release microparticle injection; Another kind is that suspending agent is not mixed in special solvent or common solvent for the sustained-release microparticle (A) of " 0 ", obtains corresponding sustained-release microparticle injection; Another is that sustained-release microparticle (A) is mixed in common solvent, adds the suspending agent mixing then, obtains corresponding sustained-release microparticle injection.Except, also can earlier sustained-release microparticle (A) be mixed and in special solvent, make corresponding suspension, with the moisture in ways such as the vacuum drying removal suspension, special solvent of reuse or common solvent suspendible obtain corresponding sustained-release microparticle injection afterwards then.Above method just is illustrative rather than definitive thereof the present invention.It should be noted that suspended drug or sustained-release micro-spheres (or microcapsule) concentration in injection decide because of specifically needing, can be, but be not limited to, 10-400mg/ml, but be preferably with 30-300mg/ml, with 50-200mg/ml most preferably.The viscosity of injection is 50cp-1000cp (20 ℃-30 ℃ time), preferred 100cp-1000cp (20 ℃-30 ℃ time), most preferably 200cp-650cp (20 ℃-30 ℃ time).This viscosity is applicable to 18-22 injection needle and special bigger (to 3 millimeters) injection needle of internal diameter.
Sustained-release micro-spheres also can be used for preparing sustained-release implant, used pharmaceutic adjuvant can be any or multiple material in the above-mentioned pharmaceutic adjuvant, but with the high molecular weight water soluble polymer is main separation, in various high molecular polymers, with polylactic acid, certain herbaceous plants with big flowers diacid, the mixture or the copolymer that contain the macromolecule polymer of polylactic acid or certain herbaceous plants with big flowers diacid is first-selection, mixture and copolymer can be selected from, but be not limited to the mixture or the copolymer of the mixture of PLA, PLGA, PLA and PLGA, certain herbaceous plants with big flowers diacid and fragrant polyanhydride or aliphatic polyanhydride.Polylactic acid (PLA) is 10/90-90/10 (weight) with the blend ratio of polyglycolic acid, preferably 25/75-75/25 (weight).The method of blend is arbitrarily.Content when glycolic and lactic acid copolymerization is respectively percentage by weight 10-90% and 90-10%.The representative of fragrance polyanhydride is to carboxy phenyl propane (p-CPP), content during to carboxy phenyl propane (p-CPP) and the copolymerization of certain herbaceous plants with big flowers diacid is respectively percentage by weight 10-60% and 20-90%, the blend weight ratio is 10-40: 50-90, preferably weight ratio 15-30: 65-85.
Therefore, another form of slow releasing agent of the present invention is that slow releasing agent is a sustained-release implant.The effective ingredient of tuberculosis implant can be packaged in the whole pharmaceutic adjuvant equably, also can be packaged in carrier holder center or its surface; Can effective ingredient be discharged by direct diffusion and/or the mode of degrading through polymer.
The characteristics of sustained-release implant are that used slow-release auxiliary material removes the high molecular polymerization beyond the region of objective existence, also contain above-mentioned any one or multiple other adjuvant.The pharmaceutic adjuvant that adds is referred to as additive.Additive can be divided into filler, porogen, excipient, dispersant, isotonic agent, preservative agent, blocker, solubilizing agent, absorption enhancer, film former, gellant etc. according to its function.
The Main Ingredients and Appearance of sustained-release implant can be made into multiple dosage form.As, but be not limited to capsule, slow releasing agent, implant, slow releasing agent implant etc.; Be multiple shape, as, but be not limited to granule, pill, tablet, powder, granule, sphere, bulk, needle-like, bar-shaped, column and membranaceous.In various dosage forms, serve as preferred slowly to discharge implant in the body.The volume size depends on factors such as the position, size of focus.Can be the bar-shaped of 0.1-5mm (slightly) * 1-10mm (length), also can be other shapes such as lamellar.
The most preferred dosage form of sustained-release implant is that the slow releasing agent that biocompatibility, degradable absorb is implanted, and can make different shape and various dosage form because of the clinical needs of difference.The packing method of its Main Ingredients and Appearance and step in United States Patent (USP) (US5651986) have a detailed description, comprise the some kinds of methods that prepare slow releasing preparation: as, but be not limited to, (i) carrier holder powder and medicament mixed be pressed into implant then, promptly so-called mixing method; (ii) carrier holder fusing, mix solid cooled then, promptly so-called fusion method mutually with medicine to be packaged; (iii) the carrier holder is dissolved in the solvent, medicine dissolution to be packaged or be scattered in the polymer solution, evaporating solvent then, drying, promptly so-called dissolution method; (iv) spray drying method; And (v) freeze-drying etc.
The effective ingredient and the percentage by weight of sustained-release implant of the present invention are preferably as follows:
Anti-tuberculosis drugs 2-50%
Slow-release auxiliary material 50-98%
Suspending agent 0.0-30%
Anti-tuberculosis drugs and percentage by weight thereof in the tuberculosis sustained-release micro-spheres of the present invention are preferably as follows:
(1) rifampicin of 5-40%, rifamycin, rifapentine or utilize the cloth spit of fland;
(2) rifamycin of the rifampicin of 5-40% and 5-40%, rifapentine or utilize the combination in cloth spit of fland;
(3) rifapentine of the rifamycin of 5-40% and 5-40% or utilize the combination in cloth spit of fland;
(4) combination that utilizes the cloth spit of fland of the rifapentine of 5-40% and 5-40%.
The percentage by weight of the slow-release auxiliary material in the tuberculosis sustained-release micro-spheres of the present invention is preferably as follows:
(1) PLA of 55-90%;
(2) PLGA of 50-90%;
(3) polifeprosan of 50-85%;
(4) bis-fatty acid of 55-90% and decanedioic acid copolymer; Or
(5) EVAc of 55-90%.
In addition, selected adjuvant also can be above-mentioned any one above combination.
The present invention can be used to prepare the pharmaceutical preparation of the various tuberculosis for the treatment of people and animal, is mainly slow releasing injection or sustained-release implant.Though the drug prepared preparation can be used for whole body tuberculosis such as phthisical treatment, local lesion serves as preferred with treatment.Common local lesion or be referred to as the outer tuberculosis of lung and mainly comprise: tuberculoma, lymphoid tuberculosis, tuberculosis of bone and joint, synovial tuberculosis, tuberculous osteomyelitis, renal tuberculosis, tuberculosis of skin, tuberculosis of intestine, tuberculosis of breast, genital tuberculosis (fallopian tube, endometrium, testis, epididymis), tuberculosis of anus, tuberculosis of thyroid gland, tuberculosis of pericardium, thoracic tuberculosis, tuberculosis fistula road, tuberculous pleuritis etc.In addition, local lesion also comprises chronic fibro cavernous pulmonary tuberculosis and the chronic pathological changes that causes because of tuberculosis or merge, as: but be not limited to serious symptom decubital ulcer, intractable cutaneous ulcer, diabetic foot, femur head necrosis and old prostate class disease etc.
Route of administration depends on multiple factor, for obtain valid density in position, tuberculosis place, medicine can give through number of ways, as in subcutaneous, intracavity (in abdominal cavity, thoracic cavity and canalis spinalis), focus week or intralesional injection or placement, the lymph node and injection in the bone marrow, but sustained-release implant is with focus local injection (slow releasing injection) or to place (sustained-release implant) serve as preferred.Can or place in when operation or perioperatively injection; Can be through apparatus interventional therapys such as fibre bronchus mirrors, as the treatment pulmonary tuberculosis cavity; But also percutaneous puncture intralesional administration interventional therapy; But also intraarticular injection or placement; Can separate application with systemic chemotherapy while or front and back, but the whole body antituberculosis therapy of a week to several months is preferably arranged before and after the topical application.
Dosage is different different because of the medicine composition, does not wait but a medicine total amount can be 10% to 200% of conventional route day dosage.When two kinds of medication combined application, the dosage of each medicine surpasses 100% of its dosage conventional route day.If focus is not removed fully or improved, can consider to place once more after 20 to 40 days or the injection slow releasing agent.For preventing that the intralesional tulase from sending out, should be equipped with the whole body administration before and after each topical.
Also can add other medicinal ingredient in slow releasing injection that the present invention is made or the sustained-release implant, as, but be not limited to antibiotics, antalgica, anticoagulant medicine, hemorrhage etc.
By following test and embodiment technical method of the present invention is further described:
The local drug concentration that test 1, different modes are used behind the anti-tuberculosis drugs (rifampicin) compares
With the rat is subjects, will accept equivalent rifampicin (10 milligrams) through following different modes respectively after its grouping: group 1, the common rifampicin injection of lumbar injection; Group 2, the common rifampicin injection of hypochondrium subcutaneous injection; Group 3, hypochondrium subcutaneous injection rifampicin slow releasing injection; Group 4, hypochondrium subcutaneous placement rifampicin sustained-release implant.Measure topical place drug level after one week, two weeks, three weeks respectively.The result shows, the local drug concentration significant difference after different modes is used, and topical can obviously improve, and effectively keeps the active drug concentration of medicine-feeding part.It is best with the effect of injection slow releasing injection wherein to place sustained-release implant with the part.Yet, local injection slow releasing injection operation most convenient, easy.This discovery constitutes key character of the present invention.Following correlation test has further confirmed this point.
The interior bacteriostasis of body that test 2, different modes are used behind the anti-tuberculosis drugs compares
With the rat is subjects, with 2 * 10
5Individual staphylococcus aureus is injected in its femur bone marrow intracavity, and the grouping (10/group) according to test 1 after the week awards the equivalent rifampicin treatment.Check inflammatory activity such as local redness subsequently, put to death animal after 30 days and get local bone marrow inspection bacterium.The result shows that injection rifampicin slow releasing injection and placement rifampicin sustained-release implant group effect are best, and first week beginning after treatment of local redness is obviously dwindled, and all animals do not have death.In the common rifampicin injection of lumbar injection group, dead in 80% animal 20 days; In the common rifampicin injection of local injection group, dead in 20% animal 20 days, but dead in 60% animal 30 days.Relatively fungistatic effect shows, the difference between the effects after different modes is used is remarkable, and topical can obviously improve and effectively keep the active drug concentration at position, place, and it is best with the effect of injection slow releasing injection wherein to place sustained-release implant with the part.But, injection slow releasing injection operation most convenient, easy.Good effect not only, toxic and side effects is also little.
The interior bacteriostasis of body that test 3, different approaches are used rifampicin compares
With the rat is subjects, and repeated trials 2 the results are shown in Table 1
Table 1
| Test group (n) | Suffered treatment | Animal dead rate (%) | The P value |
| 1 (10) | Contrast | 0 | |
| 2 (10) | The common rifampicin injection of lumbar injection | 100 | |
| 3 (10) | The common rifampicin injection of local injection | 70 | ＜0.05 |
| 4 (10) | Local injection rifampicin slow releasing injection | 10 | ＜0.01 |
| 5 (10) | The local rifampicin sustained-release implant of placing | 0 | ＜0.01 |
Above result shows, anti-tubercular drug, rifampicin is through the bacteriostasis difference of different approaches administration, is (P＜0.05), wherein local injection rifampicin slow releasing injection and local better effects if of placing the rifampicin sustained-release implant well with the effect of topical application.
The interior bacteriostasis of body that test 4, different approaches are used rifampicin compares
With the rat is subjects, repeated trials 3, but observe animal to the administration 60 days, the results are shown in Table 2
Table 2
| Test group (n) | Suffered treatment | Animal dead rate (%) | The P value |
| 1 (10) | Contrast | 0 | |
| 2 (10) | The common rifampicin injection of lumbar injection | 100 | |
| 3 (10) | The common rifampicin injection of local injection | 100 | |
| 4 (10) | Local injection rifampicin slow releasing injection | 60 | |
| 5 (10) | The local rifampicin sustained-release implant of placing | 20 | ＜0.01 |
Above result shows, anti-tubercular drug, rifampicin is through the bacteriostasis difference of different approaches administration, with the effect of topical application for well, wherein local injection rifampicin slow releasing injection and local better effects if of placing the rifampicin sustained-release implant.But local effect of placing the rifampicin sustained-release implant is good (P＜0.01) than the effect of local injection rifampicin slow releasing injection.
Same obvious treatment effect also sees local the placement and the rifampicin analog slow releasing agent of local injection: rifamycin, rifapentine and utilize the cloth spit of fland.
The potentiation of test 5, different pharmaceutical associating
Get 2 * 10
5Individual tubercule bacillus is cultivated after 24 hours and handled 24 hours with same concentration (5ug/ml) different pharmaceutical, detects inhibitory rate of cell growth (%), the results are shown in Table 3
The potentiation (suppression ratio %) of table 3 different pharmaceutical associating
Test 5 results and show, antituberculotic rifampicin and the independent application of rifampicin analog all have tangible bacteriostasis, but the effect of use in conjunction is (P＜0.01) well.
In a word, local placement and local injection rifampicin or rifampicin analog slow releasing agent all have the obvious suppression effect to bacterial growth, and the significant therapeutical effect that is shown is relevant with its local active drug concentration that obtains.Therefore, the effective ingredient of slow releasing agent of the present invention is rifampicin or any one rifampicin analog.Used rifampicin analog can be but is not limited to rifamycin, rifapentine and utilizes the cloth spit of fland.
The medicine that contains above effective ingredient can be made into sustained-release micro-spheres, and then makes slow releasing injection and implant, serves as preferred with the suspensoid injectio that is combined to form with the special solvent that contains suspending agent wherein.
Slow releasing injection or sustained-release implant also can be further specified by following embodiment.Just the invention will be further described for the foregoing description and following examples, is not its content and use are imposed any restrictions.
(4) specific embodiment
Embodiment 1.
With 90,90 and 80mg polifeprosan (to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) is 20: 80) copolymer put into (first), (second) and (the third) three container respectively, add 100 milliliters of dichloromethane then in each, behind the dissolving mixing, add 10mg rifampicin, 10mg rifamycin, 10mg rifampicin and 10mg rifamycin respectively, shake up the back contains 10% rifampicin, 10% rifamycin and 10% rifampicin and 10% rifamycin with spray drying method for preparation injectable microsphere again.Then microsphere is suspended in the normal saline that contains 15% mannitol, makes corresponding suspension type slow releasing injection.The viscosity of injection is 300cp-600cp (20 ℃-30 ℃ time).The drug release time of this slow releasing injection in external normal saline is 15-20 days, is about 30-40 days at the subcutaneous drug release time of mice.
Embodiment 2.
The method step that is processed into slow releasing injection is identical with embodiment 1, but different is that contained tuberculosis effective ingredient and percentage by weight thereof are:
(a) rifampicin of 2-40%, rifamycin, rifapentine or utilize the cloth spit of fland;
(b) rifamycin of the rifampicin of 2-40% and 2-40%, rifapentine or utilize the combination in cloth spit of fland;
(c) rifapentine of the rifamycin of 2-40% and 2-40% or utilize the combination in cloth spit of fland;
(d) combination that utilizes the cloth spit of fland of the rifapentine of 2-40% and 2-40%.
Embodiment 3.
With 70mg molecular weight peak value 65000 polylactic acid (PLGA, 75: 25) put into (first), (second) and (the third) three container respectively, add 100 milliliters of dichloromethane then in each, behind the dissolving mixing, in three containers, add 30mg rifampicin, 30mg rifapentine, 15mg rifampicin and 15mg rifapentine respectively, shake up the back contains 30% rifampicin, 30% rifapentine, 15% rifampicin and 15% rifapentine with spray drying method for preparation injectable microsphere again.Dried microsphere is suspended in the normal saline that contains 1.5% sodium carboxymethyl cellulose, makes corresponding suspension type slow releasing injection.The viscosity of injection is 300cp-600cp (20 ℃-30 ℃ time).The drug release time of this slow releasing injection in external normal saline is 10-15 days, is about 20-30 days at the subcutaneous drug release time of mice.
Embodiment 4
The method step that is processed into slow releasing injection is identical with embodiment 3, but different is that contained tuberculosis effective ingredient and percentage by weight thereof are:
(a) rifampicin of 2-40%, rifamycin, rifapentine or utilize the cloth spit of fland;
(b) rifamycin of the rifampicin of 2-40% and 2-40%, rifapentine or utilize the combination in cloth spit of fland;
(c) rifapentine of the rifamycin of 2-40% and 2-40% or utilize the combination in cloth spit of fland;
(d) combination that utilizes the cloth spit of fland of the rifapentine of 2-40% and 2-40%.
Embodiment 5.
(EVAc) puts into container with the 70mg ethylene vinyl acetate copolymer, after adding 100 milliliters of dichloromethane dissolving mixings, add 20 milligrams of rifampicin and 10 milligrams and utilize the cloth spit of fland, shake up the back again and contain the injectable microsphere that 20% rifampicin and 10% utilizes the cloth spit of fland with spray drying method for preparation.Then microsphere is suspended in the injection that contains the 5-15% sorbitol, makes corresponding suspension type slow releasing injection.The drug release time of this slow releasing injection in external normal saline is 10-15 days, is about 20-30 days at the subcutaneous drug release time of mice.
Embodiment 6.
The method step that is processed into slow releasing injection is identical with embodiment 5, but different is that contained tuberculosis effective ingredient is:
The combination of the rifampicin that utilizes cloth spit of fland and 10-20%, rifamycin or the rifapentine of 10-20%.
Embodiment 7.
70mg polifeprosan (to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) is 20: 80) copolymer is put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 20mg rifamycin and 10mg rifapentine, shake up the back contains 20% rifamycin and 10% rifapentine with spray drying method for preparation injectable microsphere again.Microsphere is suspended in the normal saline that contains 1.5% sodium carboxymethyl cellulose and 0.5% Tween 80 then, makes corresponding suspension type slow releasing injection.The drug release time of this slow releasing injection in external normal saline is 10-15 days, is about 20-30 days at the subcutaneous drug release time of mice.
Embodiment 8.
The method step that is processed into slow releasing injection is identical with embodiment 7, but different is that contained tuberculosis effective ingredient is:
The rifapentine of 10-20% and the rifampicin of 10-20%, rifamycin or utilize the combination in cloth spit of fland.
Embodiment 9
70mg polifeprosan (to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) is 20: 80) copolymer is put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 15mg rifapentine and 15mg rifampicin, shake up the back again and contain 15% rifapentine and 15% rifampicin injectable microsphere with spray drying method for preparation.Then microsphere is suspended in the normal saline that contains 1.5% sodium carboxymethyl cellulose and 15% sorbitol and 0.2% Tween 80, makes corresponding suspension type slow releasing injection.The drug release time of this slow releasing injection in external normal saline is 10-15 days, is about 20-30 days at the subcutaneous drug release time of mice.
Embodiment 10
The method step that is processed into slow releasing injection is identical with embodiment 9, but different is that contained tuberculosis effective ingredient is:
15% rifampicin and 15% rifapentine, rifamycin or utilize the combination in cloth spit of fland.
Embodiment 11
70mg polifeprosan (to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) is 20: 80) copolymer is put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 10mg rifampicin and 20mg rifapentine, shake up the back contains 10% rifampicin and 20% rifapentine with spray drying method for preparation injectable microsphere again.Then microsphere is made corresponding sustained-release implant through pressed disc method.The drug release time of this sustained-release implant in external normal saline is 10-15 days, is about 30-40 days at the subcutaneous drug release time of mice.
Embodiment 12
The method step that is processed into sustained-release implant is identical with embodiment 11, but different is that contained tuberculosis effective ingredient is:
The rifampicin of 10-20% and the rifapentine of 10-20%, rifamycin or utilize the combination in cloth spit of fland.
Embodiment 13
With 70mg molecular weight peak value 45000 polylactic acid (PLGA, 50: 50) put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 10mg rifampicin and 20mg rifapentine, shake up the back contains 10% rifampicin and 20% rifapentine with spray drying method for preparation injectable microsphere again.Then microsphere is made corresponding sustained-release implant through pressed disc method.The drug release time of this sustained-release implant in external normal saline is 15-25 days, is about 35-50 days at the subcutaneous drug release time of mice.
Embodiment 14
The method step that is processed into sustained-release implant is identical with embodiment 11,13, but different is that contained tuberculosis effective ingredient and percentage by weight are:
(a) rifampicin of 2-40%, rifamycin, rifapentine or utilize the cloth spit of fland;
(b) rifamycin of the rifampicin of 2-40% and 2-40%, rifapentine or utilize the combination in cloth spit of fland;
(c) rifapentine of the rifamycin of 2-40% and 2-40% or utilize the combination in cloth spit of fland;
(d) combination that utilizes the cloth spit of fland of the rifapentine of 2-40% and 2-40%.
Embodiment 15
The method step that is processed into slow releasing agent is identical with embodiment 1-14, but different is used slow-release auxiliary material is one of following or its combination:
A) the molecular weight peak value is 10000-30000,30000-60000,60,000 100000 or the polylactic acid (PLA) of 100000-150000;
B) the molecular weight peak value is the polyglycolic acid of 10000-30000,30000-60000,60000-100000 or 100000-150000 and the copolymer of hydroxyacetic acid (PLGA), and wherein, the ratio of polyglycolic acid and hydroxyacetic acid is 50-95: 50-50;
C) ethylene vinyl acetate copolymer (EVAc);
D) 10: 90,20: 80,30: 70,40: 60,50: 50 or 60: 40 to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) copolymer (polifeprosan);
E) bis-fatty acid and decanedioic acid copolymer;
F) poly-(erucic acid dimer-decanedioic acid) copolymer;
G) poly-(fumaric acid-decanedioic acid) copolymer;
H) xylitol, oligosaccharide, chrondroitin, chitin, potassium salt, sodium salt, hyaluronic acid, collagen protein, gelatin or white tempera.
Embodiment 16
The method step that is processed into slow releasing injection is identical with embodiment 1-10, but different is used suspending agent is respectively one of following or its combination:
A) 0.5-3.0% carboxymethyl cellulose (sodium);
B) 5-15% mannitol;
C) 5-15% sorbitol;
D) 0.1-1.5% surfactant;
E) 0.1-0.5% polysorbas20;
F) (iodine) glycerol, simethicone, propylene glycol or carbomer;
G) 0.5-5% sodium carboxymethyl cellulose+0.1-0.5% soil temperature 80;
H) 5-20% mannitol+0.1-0.5% soil temperature 80; Or
I) 0.5-5% sodium carboxymethyl cellulose+5-20% sorbitol+0.1-0.5% soil temperature 80.
Above embodiment only is used for explanation, and is not limitation application of the present invention.
The present invention disclosed and the protection the content see claim.
Claims (3)
1. slow released antituberculotic preparation is characterized in that this slow released antituberculotic preparation is a slow releasing injection, is grouped into by following one-tenth:
(1) the tuberculosis effective ingredient is that 10% rifampicin and 10% rifamycin, slow-release auxiliary material are to carboxy phenyl propane in the sustained-release micro-spheres: decanedioic acid is 20: 80 a polifeprosan, solvent is the normal saline that contains 15% mannitol, in the time of 20 ℃-30 ℃, the viscosity of injection is 300cp-600cp; Or
(2) the tuberculosis effective ingredient is that 15% rifampicin and 15% rifapentine, slow-release auxiliary material are 65000 polylactic acid for the molecular weight peak value in the sustained-release micro-spheres: hydroxyacetic acid is 75: 25 polylactic acid and a co-glycolic acid, solvent is the normal saline that contains 1.5% sodium carboxymethyl cellulose, in the time of 20 ℃ 30 ℃, the viscosity of injection is 300cp-600cp;
Sustained-release micro-spheres is weight percentage.
2. the tuberculosis slow releasing injection according to claim 1 is characterized in that the sustained-release micro-spheres in the tuberculosis slow releasing injection also is used to prepare sustained-release implant.
3. slow released antituberculotic preparation is characterized in that this slow released antituberculotic preparation is the tuberculosis sustained-release implant, is grouped into by following one-tenth:
(1) the tuberculosis effective ingredient is 10% rifampicin and 20% rifapentine, and slow-release auxiliary material is to carboxy phenyl propane: decanedioic acid is 20: 80 a polifeprosan; Or
(2) the tuberculosis effective ingredient is 10% rifampicin and 20% rifapentine, and slow-release auxiliary material is 45000 polylactic acid for the molecular weight peak value: hydroxyacetic acid is 50: 50 polylactic acid and a co-glycolic acid;
Below all be weight percentage.
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| CN102228439B (en) * | 2011-06-21 | 2013-01-02 | 中国人民解放军第三0九医院 | Gel microsphere capable of being injected with rifamycinoid antibiotics and preparation method thereof |
| EP3634583A4 (en) * | 2017-06-06 | 2021-03-03 | Merck Sharp & Dohme Corp. | Long-action implant for treatment of infectious diseases |
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