CN101836995A - Compound sulfamonomethoxine sodium multivesicular liposome and preparation method thereof - Google Patents
Compound sulfamonomethoxine sodium multivesicular liposome and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a compound sulfamonomethoxine sodium multivesicular liposome and a preparation method thereof. The compound sulfamonomethoxine sodium multivesicular liposome is prepared from lipid, sulfamonomethoxine sodium as a hydrophilic medicament and trimethoprim as a lipophilic medicament, wherein the sulfamonomethoxine sodium and the trimethoprim are simultaneously packaged in the multivesicular liposome structure formed from soya bean lecithin, cholesterol and triacylglycerol; when the multivesicular liposome is synthesized, the addition ratio of the total mass of the sulfamonomethoxine sodium and the trimethoprim to the total mass of lipid is preferably 1:4; the added mass ratio of the sulfamonomethoxine sodium to the triacylglycerol is preferably 4:1; the added mass ratio of the soya bean lecithin to the cholesterol is prefertably 1:1; and the use level of the triacylglycerol is preferably 16/mmol*L-1. During preparation, the ratio of the first emulsification time to the second emulsification time is preferably 4:1 (12 min:3 min). In the liposome, two medicaments with different dissolving characteristics of water solubility and lipid solubility are mixed together to be applied to the same multivesicular liposome; and the multivesicular liposome has the advantages of long slow releasing time, high packaging rate, good stability, can be used as a new preparation of veterinary medicine and lays foundations for clinical generalization and application.
Description
Technical field
The invention belongs to field of biological pharmacy, be specifically related to compound sulfamonomethoxine sodium multivesicular liposome and preparation method thereof.
Background technology
Sulphonamides is the antimicrobial drug of a class synthetic, since nineteen thirty-five is found, has brought into play huge effect in the control bacterial infection disease.Has has a broad antifungal spectrum; Advantages such as stable in properties is convenient to long preservation, and is cheap.As: sulfamonomethoxine sodium is N-(6-methoxyl group-4-pyrimidine radicals)-4 aminobenzenesul fonamide sodium salt monohydrates.The acetylation rate is low in the body, thereby antibacterial efficacy is stronger in vivo, and lessly causes the particularly infringement of kidney of urinary tract; Post-absorption for oral administration is good, and blood level is higher, but valid density is held time and lacked (pig 5.8 hours, goat 7 hours, sheep 2 hours); Pig toxoplasmosis, bowel oedema disease and domestic animal coccidiosis etc. all there are curative effect preferably, are usually used in infection of livestock and poultry caused by sensitive bacteria.
The Trimethoprim trimethoprim (TMP) of sulfa drugs is faint yellow or white crystalline powder; Odorless, mildly bitter flavor; Water-soluble hardly, be soluble in acid and organic solvent.Oral or the injection post-absorption rapid, the weak point of holding time.The same sulphonamides of antibacterial action, but; The two share, and can make the antibacterial action of sulfa drugs increase several times to tens times, and can present bactericidal action, and sulfonamides is had chemical sproof bacterial strain, also can potentiation; Can also strengthen the antibacterial efficacy of various antibiotic such as tetracycline, penicillin and erythromycin in addition.In clinical practice, often share with sulphonamides with 1: 5.The trimethoprim list time spent may occur drug resistance rapidly at some bacterial strain, but toxicity is very low, and therapeutic dose tangible toxic reaction can not occur.Sulfamonomethoxine sodium and trimethoprim The combined are used, and make sulfa drugs in today that the antimicrobial new drug continues to bring out, still extensive use clinically.
Antibacterial action significantly strengthens although sulfamonomethoxine sodium cooperates the back with trimethoprim, clinical practice is comparatively extensive, but still has some defectives in clinical practice, and is shorter as its half-life, owing to be antibacterial, initial dose will double and need continuous repetitively administered.Still have certain side effect, often show as: depressed, the loss of appetite of spirit or useless exhausted, anemia, leukopenia, oliguria or anuria, hematuria and fervescence etc.; The excessive use of birds can cause large quantities of death, or sees that weightening finish is slowed down, egg production descends and cause vitamin B because of alteration of intestinal flora
1, the K polyneuritis and the general hemorrhage that absorb to reduce produce.This medicine easily produces bone marrow depression, leukopenia, thrombocytopenia etc. in addition, and this medicine can produce higher toxicity when compromised immune was hindered.Therefore, reasonably medication, raising clinical efficacy, reduction adverse drug reaction have just become the act when thing.
Liposome (liposome) is that phospholipid relies on hydrophobic association to act on a kind of molecular assembly assembly of spontaneous formation in the water, be the multilamellar vesicle structure, every layer is the lipoid bimolecular film, and interlayer and liposome kernel are water, be oil phase between bimolecular film, film thickness is about 4nm.Just because of existing water has oil phase again, this fundamental property provides foundation for the hydrophilic and oleophilic pharmaceutical pack is rolled in the same liposome.And because its particle size is in nano level Jie and sees scope, physics, chemical property that many uniquenesses are arranged, it is by phospholipid spontaneous formation in water, and preparation technology is simple, has characteristics such as nontoxic, non-immunogenicity, degradable, slow release in human body, contained medicine is extensive, and reduce required dose, and strengthen its body internal stability and pharmacological action, reduce toxic and side effects, make medicine have the passive targeting feature, also can be made into immunoliposome and realize initiatively targeting.Yet the traditional liposomal of being made up of lecithin (PC) and cholesterol (Cho1) etc. is a thermodynamic unstable system, and weak stability has in vivo and in vitro limited its use, greatly influences its application as pharmaceutical carrier.
In addition, liposome is the key of performance pharmaceutical carrier effect in stability in blood.Multiple destructive factor is arranged in the blood: high density lipoprotein (HDL) is a main component of destroying liposome, aPoA-I (apoA-1) easily from HDL come off and with the liposome phospholipids incorporate, and the exchange of apoA-1 and phospholipid easily takes place in HDL and liposome, and liposome membrane forms hole; Simultaneously liposome activating complement system in blood finally forms membrane attack complex, and hydrophilic pathway appears in liposome membrane, causes drug leakage and water, electrolytically enters in a large number, finally permeates the cracking liposome; Serum albumin and liposome phospholipids incorporate form complex, reduce its stability; Phospholipase hydrolyzable phospholipid in the blood, this reaction is strong and weak to be determined by structure of phospholipid; After liposome entered blood circulation, not modified liposome major part turned round to the abundant position of mononuclear phagocyte systems such as liver and spleen (MPS), on a small quantity by lung, bone marrow and kidney picked-up; The liver plasma membrane receptor is discerned the phospholipid negative electric base that directly is exposed to the surface, thereby liposome is at first engulfed by hepatocyte.The half-life that these combined factors make traditional liposomal is tens min only.Therefore traditional liposomal still exists obvious defects as the carrier of medicine.
And multivesicular liposome (Muhivesicular liposomes, MVL) be to adopt storage storehouse foam technology (Depofoam technology, Depo-Foam) in a kind of novel lipide of nineteen eighty-three development (Britain Skyepharma PLC company) success, be mainly used in the delivery hydrophilic medicament.After the injection, discharge entrapped medicine in time as drug depot.Because above characteristics and particle are in the foamed outward appearance of microscopically, MVL is also referred to as storage storehouse foam drug delivery system.The MVL injecting pathway is extensive, can be used for injection such as eye, epidural or the articular cavity etc. of sensitive part, and the human research shows that safety is higher.In addition, the Depofoam technology is verified can carry out industrialized great production, has good storage period stability.One of main feature of multivesicular liposome is that slow-release time obviously is longer than conventional liposome, if hydrophilic drugs sulfamonomethoxine sodium and lipophilic drugs trimethoprim can be wrapped in the same multivesicular liposome, and the pharmacological action that performance is good; The research report that does not also have at present this respect.
Summary of the invention
Purpose of the present invention aims to provide a kind of selection and simple to operate hydrophilic drugs sulfamonomethoxine sodium and lipophilic drugs trimethoprim is wrapped in preparation method in the same multivesicular liposome.
Another purpose of the present invention aims to provide the compound sulfamonomethoxine sodium multivesicular liposome of method for preparing, its slow-release time length, hydrophilic drugs sulfamonomethoxine sodium and lipophilic drugs trimethoprim are wrapped in the same multivesicular liposome, envelop rate height, good stability, can be used as the veterinary drug novel form, for clinical application lays the first stone.
Compound sulfamonomethoxine sodium multivesicular liposome of the present invention is by lipid: wrapped up hydrophilic medicament sulfamonomethoxine sodium and lipophilic drugs trimethoprim in the multivesicular liposome structure that soybean lecithin, cholesterol and triacylglycerol form simultaneously; Folliculus particle size range 10-40 μ m in the described multivesicular liposome; During synthetic described multivesicular liposome, the adding proportion of the gross mass of sulfamonomethoxine sodium and trimethoprim gross mass and lipid is 1: 4-1: 10, be preferably 1: 4; The interpolation mass ratio of sulfamonomethoxine sodium and trimethoprim is 10: 3-4: 1, be preferably 4: 1; The interpolation mass ratio of soybean lecithin and cholesterol is 1-4: 1, be preferably 1: 1; The consumption of triacylglycerol is 8-16/mmolL
-1, be preferably 16/mmolL
-1
The preparation method of above-mentioned compound sulfamonomethoxine sodium multivesicular liposome may further comprise the steps:
(1) taking by weighing soybean lecithin, cholesterol, trimethoprim, triacylglycerol in proportion is dissolved in the 10-15mL chloroform and forms lipoprotein solution;
(2) sulfamonomethoxine sodium is dissolved in the 10-15mL ultra-pure water forms aqueous solution;
(3) with lipoprotein solution and aqueous solution, vortex vibration 1-10min, emulsifying 2-12min forms the w/o type colostrum on the ultrasonic cell-break machine then;
(4) get w/o type colostrum 5-10mL, add ultra-pure water 10-15mL, the 1-10min that on the vortex mixed instrument, vibrates, ultrasonic emulsification 2-5min; Form W/O/W type emulsion;
(5) get above-mentioned W/O/W type emulsion and on rotary evaporator, vapor away chloroform, promptly get compound sulfamonomethoxine sodium multivesicular liposome.
Also adding Vit-E in the step (1) is dissolved in the chloroform.
Step (1) forms lipoprotein solution in 25-30 ℃ of water-bath.
Step (3) is at emulsifying preincubation 2-5min.
Add Tween-80 and Span-80 again after adding ultra-pure water in the step (4), on the vortex mixed instrument, vibrate.
The rotary evaporation temperature is 45-50 ℃ in the step (5), time 10-20min.
Multivesicular liposome is a kind of novel medicament slow releasing preparation, compares with traditional liposome, and it has numerous advantages such as envelop rate height, envelope volume is big, drug leakage is few.Relative traditional liposomal, in the lipid components of multivesicular liposome except both sexes phospholipid such as phospholipid, still need and add neutral phospholipid of at least one such as triacylglycerol, their no film forming abilities but can be filled in the hydrophobic space of lipid bilayer intersection, stablize the connection of infall, can also be dispersed in the water compartment with little oil droplet form, have discontinuous drug solution vesicle after making liposomal encapsulated medicine, thereby have and more seal volume and bigger particle diameter.The non-concentric structure of multivesicular liposome lipid layer can make the stability of liposome increase, and pharmaceutical release time prolongs.The reason that influences the compound sulfamonomethoxine sodium multivesicular liposome envelop rate in preparation process mainly is the compactness of breaking of emulsion and polymerization and film etc., the composition of film material can influence the rigidity of film, the rigidity deficiency, film easily breaks, and obtains unsettled multivesicular liposome.So the present invention adopts multi-emulsion method to prepare multivesicular liposome, having screened suitable film material forms and emulsification condition, make the typical multivesicular liposome structure of multivesicular liposome observation visible " big capsule bag folliculus " under ordinary optical microscope and under the projection electron microscope of preparation, envelop rate is up to 86.2%.Except add membrane stabilizer in oil phase, outside Vit-E, aqueous phase also adds coemulsifier (as Tween-80 and Span-80) and stablizes emulsion outside in the process of preparation liposome; Otherwise then easily polymerization is lumpd, and can not get multivesicular liposome.
The film of multivesicular liposome is that preparation temperature and solvent evaporates speed directly influence the formation of multivesicular liposome along with the volatilization of organic solvent forms at former oil phase position.Temperature is too high or too low during preparation, removes organic solvent excessive velocities or slow excessively, all causes emulsion promptly to break before changing into multivesicular liposome easily, finally can't form multivesicular liposome.In preparation process, preferably remain identical temperature, avoid the surface tension of medium and the HLB value of surfactant to change along with variation of temperature, influence the stability of emulsion.The present invention has investigated the encystation situation under the condition of different temperatures, and it is 25-30 ℃ that temperature is controlled in final selection all the time, and the gained emulsion is more stable, and the scrotiform shape is better.
Adopt the multi-emulsion method method as the compound sulfamonomethoxine sodium multivesicular liposome preparation method, this also is the unique method for preparing multivesicular liposome at present.The control of emulsification condition is a very important factor that influences particle diameter, emulsifying for the first time is with emulsive power is the most remarkable to the influence of multivesicular liposome particle diameter for the second time, emulsifying is for the first time adopted high-power, the emulsification condition proper extension, power is less for the second time, emulsification times suitably shortens, and can increase the particle diameter of multivesicular liposome like this, and vice versa.According to these conditions, take suitable emulsification condition, control particle diameter.
The factor that influences compound sulfamonomethoxine sodium multivesicular liposome formation and envelop rate, content in the process of preparation is a lot, wherein principal element is the ratio of soybean phospholipid-cholesterol, if the phospholipid consumption is too many, the cholesterol consumption very little, the poor stability of liposome then; Otherwise liposome is difficult for forming; Next is the ratio of liposome membrane material-medicine, if the film material use quantity is many, medication amount is few, though liposome to the envelop rate height of medicine, the content of dispersion of liposome is few, causes the waste of liposome membrane material.
Liposome is that phospholipid etc. is dispersed in the vesicle that forms in the water, phospholipid contains hydrophilic and hydrophobic group, process itself closed in water can form bilayer, according to this principle, the present invention takes two kinds of medicines, a kind of hydrophilic medicament and a kind of lipophilic drugs make liposome in the process that forms, and can wrap up hydrophilic medicament and lipophilic drugs.Because multivesicular liposome is mainly used to the encapsulating hydrophilic medicine, sulfamonomethoxine sodium and trimethoprim also will be key factors that influences drug effect in the ratio of multivesicular liposome.So this test is in the process of design, adopt sulfamonomethoxine sodium (hydrophilic) and two kinds of medicines of trimethoprim (lipotropy), and the ratio (4: 1) that preferably differs bigger prepares compound sulfamonomethoxine sodium multivesicular liposome, obtained effect preferably.
The multivesicular liposome multivesicular liposome that the present invention prepares forms by many folliculus not of uniform size, in irregular shape are tightly packed together, is separated by bilayer lipid membrane between folliculus and the folliculus.Observation by light microscope can see that multivesicular liposome is spherical in shape, and there are many granules inside, similar cellular formation; Adopt the liposome of storage storehouse foam technology development to be suitable for sealing water soluble drug generally speaking.But medicament selection of the present invention is ingenious, preparation during multivesicular liposome except phospholipid and cholesterol, also used triacylglycerol, triacylglycerol is not to be mixed in the bilayer lipid membrane equably, but some is dispersed in the interior aqueous phase of multivesicular liposome with form distribution of a little oil droplet; Another part then is filled in the space of the lipid film cross-linking part between folliculus and the folliculus, plays a part to connect, builds bridge, stablizes internal pouch.Trimethoprim only contains 1%-2%, and is fat-soluble medicine, just is dissolved in the little oil droplet form of triacylglycerol, does not disturb the parcel of water soluble drug.Therefore, the present invention has utilized and exclusive can deliver hydrophilic medicament, can deliver the construction features of fat-soluble medicine again, has overcome the defective that multivesicular liposome only is used as the water soluble drug delivery system; And water soluble drug and fat-soluble medicine are perfectly formed multivesicular liposome.
The present invention is filled in the hydrophilic lipophilic blister cavities of liposome with different solubility drugs by certain proportioning, and this special mode of sealing has also improved the volume of sealing of liposome, and entrapment efficiency is up to more than 80%.Remedy the defective of in the past the fat-soluble medicine clinical drug effect of influence of sealing that I haven't seen you for ages; And its preparation technology is simple, the multivesicular liposome stable in properties of preparation, have important feature such as dosage is extremely low, non-immunogenicity, degradable, slow release in vivo, reduce required dose, strengthen its body internal stability and pharmacological action, (sulfamonomethoxine sodium content is extremely low but evident in efficacy in the liposome to reduce toxic and side effects; Granulesten is soybean extract, and is nontoxic), make medicine have the passive targeting feature, also can be made into immunoliposome and realize initiatively targeting.Overcome the shortcoming of the thermodynamic unstable system of the traditional liposomal of being made up of lecithin (PC) and cholesterol (Cho1) etc., granulesten is than the heat stability height of lecithin and cholesterol.
Medicine of the present invention has characteristics such as efficient, long-acting and low-residual.High efficiency of the present invention is mainly reflected in the water soluble drug sulfamonomethoxine sodium and the fat-soluble medicine trimethoprim is wrapped in integral body of formation in the same multivesicular liposome in the ratio that is fit to, given full play to the combined effect of medicine, curative effect than simple medication strengthens greatly, makes the antibacterial action of sulfamonomethoxine sodium heighten the effect of a treatment several times even tens times.The novel multivesicular liposome that its long-lasting the present invention of being mainly reflected in forms is a drug depot, slowly discharge entrapped medicine in time, just the medicament slow release time obviously is longer than conventional liposome (the maximum characteristics of multivesicular liposome is exactly long-acting, he sticks together as a lot of little liposomees, still the little complete liposome of the inside, back of breaking of outside, melt still is complete little liposome always to the end, his structure is just as foaminess, foam is broken into two with one's hands, the inside all is little complete granule,) to be mainly reflected in the multivesicular liposome that the present invention forms the content of dispersion of sulfamonomethoxine sodium and trimethoprim extremely low for its low-residual, total dosage has only the 1/10-1/100 of positive usual amounts.
Compound sulfamonomethoxine sodium multivesicular liposome of the present invention can be made into injection or oral formulations.
Description of drawings
Fig. 1 is the configuration of multivesicular liposome of the present invention;
Fig. 2 is the pharmacokinetic studies empty blood plasma chromatogram of multivesicular liposome of the present invention;
Fig. 3 is sulfamonomethoxine sodium solution chromatogram in the pharmacokinetic studies of multivesicular liposome of the present invention;
Fig. 4 extracts back sulfamonomethoxine sodium chromatogram for blood plasma in the pharmacokinetic studies of multivesicular liposome of the present invention;
Fig. 5 extracts back composite sulfamonomethoxine sodium chromatogram for blood plasma in the pharmacokinetic studies of multivesicular liposome of the present invention;
Fig. 6 is the average drug-time curve of intramuscular injection compound sulfamonomethoxine sodium multivesicular liposome in the pharmacokinetic studies of multivesicular liposome of the present invention.
The specific embodiment
Can see that from Fig. 1 a lot of little utricules assemble,, be accumulated into multivesicular liposome as foaminess being deposited in together tightly.
Following embodiment is intended to further specify the present invention, and unrestricted the present invention.
Prepared multivesicular liposome of the present invention according to the following steps.
(1) take by weighing soybean lecithin, cholesterol, trimethoprim, triacylglycerol in proportion, Vit-E is dissolved in the 10-15mL chloroform, forms lipoprotein solution in the 25-30 ℃ of water-bath;
(2) sulfamonomethoxine sodium is dissolved in the 10-15mL ultra-pure water forms aqueous solution;
(3) with lipoprotein solution and aqueous solution, vortex vibration 1-10min, 25-30 ℃ of water bath heat preservation 2-5min; Emulsifying 2-12min forms the w/o type colostrum on the ultrasonic cell-break machine then;
(4) get w/o type colostrum 5-10mL, add ultra-pure water 10-15mL, add Tween-80Span-80 again; On the vortex mixed instrument, vibrate ultrasonic emulsification 2-5min; Form W/O/W type emulsion;
(5) get above-mentioned W/O/W type emulsion and on rotary evaporator, vapor away chloroform, 45-50 ℃ of rotary evaporation temperature, time 10-20min; Promptly get compound sulfamonomethoxine sodium multivesicular liposome.
Orthogonal design is optimized compound sulfamonomethoxine sodium multivesicular liposome prescription and preparation technology
According to above-mentioned steps, the optimal conditions of the orthogonal design screening liposome preparation of four factors, four levels is used in this experiment, promptly with medicine fat than (mass ratio, wherein the mass ratio of sulfamonomethoxine sodium and trimethoprim is 4: 1), phospholipid and cholesterol than the consumption of triacylglycerol in (mass ratio), the oil phase, twice emulsification times than 4 factors, each factor is got 3 levels, as index, optimize the optimised process prescription with envelop rate.Main influence factor and level see Table 1.
Table 1 orthonormal design of experiments factor and water-glass
According to fixed four factors, four levels, by [L
9(3
4)] orthogonal design is prepared 9 duplicate samples, is to investigate index to carry out orthogonal test with the envelop rate, the result sees table 2 for details.By [L
9(3
4)] orthogonal design as seen, the influence to the compound sulfamonomethoxine sodium multivesicular liposome envelop rate in 4 factors is D＞B＞C＞A in proper order, draws to optimize prescription and be A
1B
1C
3D
3Be m (medicine): m (lipid)=1: 4; M (phospholipid): m (cholesterol)=1: 1; The consumption of triacylglycerol is 16/mmolL
-1For the first time emulsification times and for the second time the emulsification times ratio be 4: 1 (12min: 3min).
Table 2 orthonormal design of experiments result
Annotate: X
1, X
2, X
3Be respectively the average envelop rate of 3 experiments of each factor varying level; R is each factor varying level extreme difference.
According to 3 batches in the optimum prescription preparation of mathematical model optimizing gained sample, the result shows 3 batch sample envelop rate basically identicals, is respectively 86.2%, 85.1%, 83.7%, and average envelop rate is 85%, and this preparation technology's favorable reproducibility is described.
The toxicity research of compound sulfamonomethoxine sodium multivesicular liposome of the present invention
In clinical practice, sulfamonomethoxine sodium is as the potent antibacterial in the sulfa drugs, its has a broad antifungal spectrum, utilization extensively, but also show simultaneously toxic and side effects such as organ toxicity such as stronger local irritation regulating liver-QI, kidney and neuromuscular blockade, liposome is fit to vivo degradation, avirulence and immunogenicity, liposome can improve the therapeutic index of medicine as pharmaceutical carrier, reduce drug toxicity, reduce drug side effect, and have and to prolong the effective blood drug concentration time, reduce advantages such as drug dose.This experiment is started with from acute toxicity test, the subchronic toxicity test of compound sulfamonomethoxine sodium multivesicular liposome, has investigated the safety of said preparation, provides foundation for guaranteeing clinical drug safety.
Make compound sulfamonomethoxine sodium multivesicular liposome mass concentration of the present invention be 22.5mg/mL, standby.
Experimental animal
60 of SPF level kunming mices, ♀
Half and half, 18～24g/ only purchases the toy laboratory in animal medicine institute of Agricultural University Of Hunan.Room temperature is controlled at 18～22 ℃, relative humidity 40～70%, well-ventilated in the holding chamber, the male and female sub-cage rearing, cage heelpiece material uses after daylight shines for wound wood flower bits, next day cleaning mouse cage is once changed the bedding and padding and the mouse cage of sterilizing, the full nutrition solid particle Mus feedstuff that feedstuff provides for animal medicine institute of Agricultural University Of Hunan toy laboratory, wherein contain protein about 21%, free choice feeding is freely drunk water, after animal feeding 7d observes, be defined as healthy animal, can test.
Method
1) acute toxicity test
In trial test, find that compound sulfamonomethoxine sodium multivesicular liposome is with a power-carrying 1mL/ lumbar injection after, mice does not have death, can not carry out the mensuration of LD50 value, therefore carries out maximum tolerated dose and tests.On trial test basis repeatedly, get 20 of white mice, male and female half and half are divided into two groups at random, one group of injection composite sulfamonomethoxine sodium injection, dosage is 837.52mg/kg.bw
[83]Lumbar injection 0.5mL, another group (is equivalent to 85 times of composite sulfamonomethoxine sodium clinical application amount by 1700mg/kg.bw,) to the mice by intraperitoneal injection compound sulfamonomethoxine sodium multivesicular liposome, divide 3 times in 24 hours administration finish and (be subjected to the influence of preparation method, can't obtain the compound sulfamonomethoxine sodium multivesicular liposome of high concentration, so administration several times is to reach required dosage).After the administration, observe and write down animal appearance sign in 7 days, diet desire, behavioral activity, defecation, central nervous system's symptom and dead animal number.If any animal dead, postmortem is in time observed internal organs and is changed, and analyzes the dead mouse reason, if any the pathological tissues microscopy of then cutting into slices.
2) subchronic toxicity test
Carry out the dosage design according to the median lethal dose(LD 50) method and in conjunction with intending with the clinical dosage method, if high, medium and low 3 dosage groups and 1 negative control group, high dose group are 300mg/kg.bw (for 15 times of clinical application amount), middle dosage group is that 100mg/kg.bw (for 5 times of clinical application amount), low dose group are 50mg/kg.bw (for 2.5 times of clinical application amount).Get 80 of white mice, female, hero half and half is divided into 4 groups at random, and 20 every group (male and female half and half), male and female divide cage to feed.Compound sulfamonomethoxine sodium multivesicular liposome is diluted suitable multiple with sterile saline, every Mus is every other day in set time intraperitoneal injection of drugs 0.5mL, claimed a body weight every three days, adjust the extension rate of medicine according to body weight change, matched group same every day in set time intraperitoneal injection of saline 0.5mL, 4w observes clinical response continuously.4w in drug withdrawal 24 hours to each group mice carry out body weight, the hematology detects, and get and respectively organize 1/2 mice sacrificed by decapitation, carry out organ coefficient mensuration, histological examination and blood biochemical and learn detection, remaining mice drug withdrawal continues to feed the 2w time, observes and record stops the animal dead situation in the 2w time and the variation of body weight after the administration.
Observation index
(1) general physiological character is observed
Observe every day and record respectively organize mice outward appearance, activity, ingest, drink water, by signs such as natural hole such as hair, nose, oral cavity, anus and defecation, if any animal dead, postmortem in time is after the perusal, if any the pathological tissues microscopy of then cutting into slices, analyze the cause of death.
(2) growth promoter index
Claim body weight every other day one time, record data calculate mice weightening finish situation at administration 4w convalescent period (behind the 2w) respectively.
(3) peripheral blood is learned index
Tail vein blood behind the administration 4w, after blood sample was used the heparin sodium anticoagulant, the method for inspection was carried out hemoglobin (HB) routinely, erythrocyte (RBC), leukocyte (WBC) counting and classification.Blood routine examination project and method are respectively: hemoglobinometry alkalization hemoglobin photoelectric colorimetry; Erythrocyte and numeration of leukocyte adopt counting by naked eye; Microscope differential counting method is adopted in differential blood count.
(4) blood biochemical is learned and is detected
Sacrificed by decapitation animal and blood sampling behind the administration 4w, 2～3 mouse bloods are merged into a blood sample, conventional preparation serum, measure alkali phosphatase (ALP), glutamic oxaloacetic transaminase, GOT (AST), glutamate pyruvate transaminase (ALT), total protein (TP), albumin (ALB), blood urea nitrogen (BUN), creatinine indexs such as (Cre).Test kit is provided by Zhongsheng Beikong Biological Science ﹠ Technology Co., Ltd., presses the test kit description operation, goes up at semi-automatic serum biochemistry analyser (MD-110 U.S. product) and measures.
(5) system's postmortem and organ coefficient are measured
Each group is got 5 mices dissections that blood sampling is put to death at random behind the administration 4w, observes organ size, form, color and luster, texture such as the heart, liver, spleen, lung, kidney, adrenal gland, thymus, stomach, small intestinal.Core, important organs such as liver, spleen, lung, kidney carry out organ coefficient and measure organ coefficient=(organ weight in wet base/body weight) * 100%.
(6) histopathologic examination
After the heart, liver, spleen, lung, kidney cleaned up with normal saline, with 10% formalin fixed three days, paraffin embedding, section was carried out histological examination through HE dyeing under optical microscope.
Statistical disposition
To test the gained data compilation and become table, and whether judge each data in normal range, computation of mean values and standard deviation are checked the significance of difference of measuring respectively take medicine group mean and matched group mean with t.
The result
1, The acute toxicity tests
With the mice of 837.52mg/kg.wb dosage injection composite sulfamonomethoxine sodium injection, there have 6 mices to occur immediately to be listless, restlessness, and astasia, contrary upright by hair, abdominal part can not land, and muscular tremor is until tic, and dead mouse is 5 in the 7d.With the mice of 1700mg/kg.wb dosage injection compound sulfamonomethoxine sodium multivesicular liposome after administration in the 7d, do not see dead mouse is arranged, but after having mice more than 20% to inject the last time, produce that walking reduces, drowsiness symptom, recover normal after two hours.Greater than 1700mg/kg.wb, this amount is equivalent to 85 times of clinical consumption to compound sulfamonomethoxine sodium multivesicular liposome to the maximum tolerated dose of mice as can be known.The result shows that the toxicity of compound sulfamonomethoxine sodium multivesicular liposome significantly is lower than composite sulfamonomethoxine sodium.
2, subchronic toxicity test result
1) body weight and food ration change
The mice body weight is weighed and be the results are shown in Table 3 as seen from the experiment, and the variation of food ration increases with body weight and changes unanimity.Through variance analysis, each test group weight gain value is compared there was no significant difference (P＞0.05) with matched group, illustrates that each reagent group do not have obvious influence to the growth of mice under this experimental condition.
Table 3 mice doctor's type scale is decided table as a result
2) hematological examination
The testing result of mouse blood index saw Table 4. results and show that every numerical value all fluctuates within normal range, and each dosage group and matched group be there was no significant difference (P＞0.05) relatively, did not see because of drug-induced unusual.
Table 4 mouse blood is learned the index result
3) serum biochemistry is learned and is detected
The testing result of mice serum biochemical indicator sees Table 5. each test group the result of the test that influences of mice serum biochemical indicator is shown: total protein (TP), albumin (ALB) are compared the difference (P＞0.05) of no significance in each dosage group mice serum with matched group, serum alanine aminotransferase (ALT), aspartate amino transferase (AST), blood urea nitrogen (BUN), T-CHOL (TCHO), alkali phosphatase indexs such as (ALP) is compared also with matched group and is not all made significant difference.After 2 weeks of drug withdrawal, compare the difference (P＞0.05) that does not have on the statistical significance with every index behind the administration 4W.Illustrate that each reagent group hematology's biochemical indicator to mice under this experimental condition does not have obvious influence.
Table 5 mice serum biochemical indicator is table as a result
4) organ coefficient inspection
The organ coefficient of mice important organ sees Table 6, by the result as can be known, behind mice administration 4W, compares each reagent group brain, the heart, liver, spleen, lung, kidney main organs coefficient with matched group and does not all have significant difference (P＞0.05), there is no unusual.
Table 6 mice organ coefficient is table as a result
5) cut open the inspection check result
Organs such as each reagent group mouse brain of perusal, the heart, liver,spleen,kidney compare with matched group, and each internal organs size, form, color and luster texture all do not have tangible anomaly.
Important organs such as brain, the heart, liver,spleen,kidney are fixed, cut into slices after the embedding, section is carried out histological examination through HE dyeing under optical microscope, and each is organized, and white mice organs and tissues structure is normal substantially, cell dyeing is even.
(1) heart
Each group does not all have congested, necrosis and inflammatory activity.Visceral pericardium is smooth, no petechia, and myocardial thickness and color and luster no abnormality seen are not seen necrosis of myocardial cell structure or cicatrix, and cardiac valve thickness is normal, and endocardium is smooth, and coronary artery is not seen narrow or sclerosis.
(2) liver
Each group is not seen pathological changes such as hepatocellular degeneration, necrosis, inflammation, sclerosis, carcinoma, the liver surface Smooth and moist, and the lobules of liver clear in structure, portal vein district no change is not seen the mainline expansion.
(3) spleen
It is all normal that each organizes the hardness color and luster, and the tangent plane profile is neatly clear, and no abnormality seen changes.
(4) lung
Lungs size, hardness, color and luster are all no abnormal, and the tangent plane profile is neatly clear, and each group there is no edema, hemorrhage, inflammatory variation, does not see brown induration of lung, do not see that bronchus, aberrant angiogenesis change.
(5) kidney
Two kidney sizes, hardness, color and luster are all no abnormal, and tangent plane is smooth, does not see the peplos adhesion, and the tangent plane skin, that medullary substance is had a common boundary is clear, and the cortex clear-cut texture is not seen calculus in the ureter, renal artery wall no abnormality seen.Each group there is no pathological changes such as degeneration, necrosis, inflammation, atrophy, fibrosis.
More than cut open inspection and histopathologic examination and show, each organ not have the performance pathological change relevant with drug effect, illustrates that compound sulfamonomethoxine sodium multivesicular liposome group mice main organs do not have pathology and damage.
Conclusion:
1, because the toxicity of compound sulfamonomethoxine sodium multivesicular liposome is very low, and the restriction of preparation method can not obtain the liposome of high concentration, can't obtain its LD
50Heap(ed) capacity to intraperitoneal injection does not have clearly regulation yet at present, so mtd test has only been carried out in acute toxicity test roughly, the acute toxicity that has compared composite sulfamonomethoxine sodium and compound sulfamonomethoxine sodium multivesicular liposome, greater than 1700mg, this amount is equivalent to 85 times of clinical consumption to compound sulfamonomethoxine sodium multivesicular liposome to the maximum tolerated dose of mice.The result shows that the toxicity of compound sulfamonomethoxine sodium multivesicular liposome significantly is lower than composite sulfamonomethoxine sodium, illustrates also that simultaneously liposome truly has the effect that reduces drug toxicity, relatively and the conventional formulation safety range bigger.
2, in the subchronic toxicity test of compound sulfamonomethoxine sodium multivesicular liposome, vitals such as the heart, liver, spleen, lung, kidney are cutd open inspection and histopathology microscopy, the result shows, each dosage group of compound sulfamonomethoxine sodium multivesicular liposome is compared with the normal saline matched group, above-mentioned each organ and tectology are normal, inorganization is learned pathological changes, illustrates that each dosage group of compound sulfamonomethoxine sodium multivesicular liposome do not have the obvious damage effect to tissue and the organ of mice.Behind the administration 4w, organ coefficient to vitals such as each group mouse core, liver, spleen, lung, kidneys is measured, the result shows, each dosage group of compound sulfamonomethoxine sodium multivesicular liposome is compared there was no significant difference with the normal saline matched group, illustrates that compound sulfamonomethoxine sodium multivesicular liposome does not have obvious influence to the growth promoter of mice important organ.
In the subchronic toxicity test of compound sulfamonomethoxine sodium multivesicular liposome, check the mice serum biochemical indicator, comprised hemoglobin, red blood cell count(RBC), numeration of leukocyte, total protein, albumin, ALT, AST, ALP, BUN.Hemoglobin, red blood cell count(RBC), numeration of leukocyte mainly reflect the general physiological situation of mice, the result shows, high, medium and low dosage group is compared with the normal saline matched group does not all have significant difference, illustrates that the compound sulfamonomethoxine sodium multivesicular liposome liposome does not have obvious influence to the general physiological situation of mice; Total protein, albumin, ALT, AST, ALP mainly reflect the Mouse Liver function, the result shows, high, medium and low dosage group is compared with the normal saline matched group does not all have significant difference, illustrates that compound sulfamonomethoxine sodium multivesicular liposome does not have obvious influence to the liver function of mice; BUN mainly reflects mice renal function situation, and the result shows that high, medium and low dosage group is compared with the normal saline matched group does not all have significant difference, illustrates that compound sulfamonomethoxine sodium multivesicular liposome does not have influence to the renal function situation of mice.Above result shows that all compound sulfamonomethoxine sodium multivesicular liposome does not have the cumulative toxicity effect to mice, illustrates that this preparation is safe and reliable in the therapeutic dose scope.Composite sulfamonomethoxine sodium has stronger liver, nephrotoxicity, after this drug encapsulation is in liposome, because liposome has the effect that can concentrate in the disease target area, medicine also is transferred to the target area from medicine-feeding part, concentrate in the target area, less at other internal organs and tissue distribution, concentration is very low, thereby can reduce it greatly to body particularly liver, nephrotoxicity.Another major reason that compound sulfamonomethoxine sodium multivesicular liposome can reduce drug toxicity may be that liposome particles is bigger, is difficult to enter renal cortex, thereby can significantly reduce the infringement to kidney.
Compound sulfamonomethoxine sodium multivesicular liposome is in the intravital pharmacokinetic studies of rabbit
According to the data introduction, after the liposome dosage form enters the body circulation by all means, major part optionally is distributed in is rich in cytophagous reticuloendothelium system, particularly liver, spleen increase the hold-up of packaging medicine to cause some position, less skeleton, cardiac muscle and the nervous tissue of entering, therefore, the liposome dosage form can significantly change the kinetic property and the tissue distribution of medicine.Sulfamonomethoxine sodium normal injection agent at present, it is shorter to have a half-life, to shortcomings such as infection site targeting differences.After sulfamonomethoxine sodium is prepared into multivesicular liposome, can increase the targeting of infection site, reduce toxic and side effects, prolong the effective blood drug concentration time greatly.This experiment is given the rabbit intramuscular injection with compound sulfamonomethoxine sodium multivesicular liposome, adopt the HPLC method to measure the blood plasma Chinese medicine concentration of different time points in the 96h, studied compound sulfamonomethoxine sodium multivesicular liposome through the time change procedure, discuss some parameters of sulfamonomethoxine sodium.
For examination animal and medicine
6 of healthy rabbits, male and female half and half, body weight 1.6～2.2kg is available from laboratory animal portion of Hunan Medical University.Conventional raising, free choice feeding.Observe a week, clinical manifestation health.
Make compound sulfamonomethoxine sodium multivesicular liposome mass concentration of the present invention be 20mg/mL, standby.
1, plasma sample is handled
Get plasma in rabbit sample 0.5mL in 10mL tool plug centrifuge tube, add an amount of sulfamonomethoxine sodium reference substance respectively, mixing, adding ethyl acetate 3mL extracts, mix 3min on the eddy mixer, centrifugal with 3000r/min, the separating acetic acid methacrylate layer and then adds ethyl acetate and brings up again 1 time in another test tube.In and the ethyl acetate mixed liquor that extracts for 2 times, in fume hood, 40 ℃ of water-baths, N
2Air-blowing is done.Add 3mL ethyl acetate flushing tube wall again, continue water-bath and dry up, residue dissolves with 100 μ L mobile phases, gets 20 μ L sample introductions respectively.
2, the foundation of blood plasma standard curve
Precision is measured 5 parts of each 0.5mL of blank plasma, places 5 10mL tool plug centrifuge tubes respectively, and each adds not commensurability sulfamonomethoxine sodium solution, makes that sulfamonomethoxine sodium concentration in the blood plasma is respectively 0.05,0.25,1,5, the solution of 10ug/mL.
3, animals administer and blood specimen collection
Get 6 of healthy rabbits, respectively at taking before the administration about blank blood sample 4mL, place the centrifuge tube that contains heparin sodium,, take a blood sample according to the administration of 20mg/kg leg muscle with homemade compound sulfamonomethoxine sodium multivesicular liposome respectively at 0h, 1h, 6h, 12h, 18h, 24h, 36h, 48h, 60h, 72h, 84h, 96h.About each blood sampling 2mL, all blood samples all place the centrifuge tube that contains heparin sodium, mixing.Blood sample is centrifugal 15min under 2000 commentaries on classics, separated plasma, and-20 ℃ of refrigerators are preserved, and are to be measured.
4, determination of plasma concentration
Centrifugal back precision is measured 0.5mL blood plasma, after the processing, measures blood drug level in the blood plasma.
5, date processing
The calculation pharmacokinetic parameters is asked in the 3P97 pharmacokinetics software match of Chinese Pharmacological Society's establishment.
The result
1, chromatogram
The chromatogram of blank serum, sulfamonomethoxine sodium solution, sulfamonomethoxine sodium blood serum sample, composite sulfamonomethoxine natremia final proof product such as Fig. 2～shown in Figure 5, the result shows, under the condition that this test is adopted, the chromatographic peak good separation of composite sulfamonomethoxine sodium, blank serum and other impurity peaks do not have influence to it, and retention time is respectively 6.51 1min.
2, linear dependence
SMM is in 0.05～10 μ g/mL concentration range, and peak area (A) is good with drug level (C) linear relationship, standard curve equation: y=20508x+235.32 (r:0.9999), and wherein x is by being surveyed blood drug level ug/mL, and y is the peak area of SMM sodium.
3, pharmacokinetic parameter is measured
Behind the quiet notes compound sulfamonomethoxine sodium multivesicular liposome, the blood medicine mass concentration of each sample point of rabbit sees Table 7, the average drug-time curve of quiet notes compound sulfamonomethoxine sodium multivesicular liposome group is seen Fig. 6, the blood drug level data meet the intravenous injection one compartment open model after the match of 3P97 program, main pharmacokinetic parameters sees Table 8.From table, as can be known, behind administration 96h, still can detect medicine, illustrate that compound sulfamonomethoxine sodium multivesicular liposome blood drug level holds time more than 96h, have long-acting.
Table 7 compound sulfamonomethoxine sodium multivesicular liposome is different time blood drug level (μ g/mL) in the rabbit body
Table 8 compound sulfamonomethoxine sodium multivesicular liposome is at rabbit internal metabolism kinetic parameter
Conclusion
The particle diameter of multivesicular liposome is generally 5～50 μ m, common single chamber, the general particle diameter of multilamelar liposome is 0.1～5 μ m, the particle diameter of multivesicular liposome is not suitable for intravenous injection than big one to two order of magnitude of conventional liposome, so adopt intramuscular injection in the drug metabolism test, blood collection is because interval is long, do not adopt pharmacokinetics common carotid artery intubation procedure commonly used, with tame rabbit ear vein blood sampling, it is good to produce effects.
Single chamber, multilamelar liposome has identical concentric structure, multivesicular liposome does not have identical concentric circular, its inside has many not of uniform size, the very irregular folliculus of shape, these folliculus are to be deposited in closely together, a times bilayer lipid membrane separates between folliculus and the folliculus, its internal structure and foam are very alike, and this is the reason of its trade name DepoFoam.This structure has given lipid film stronger mechanical strength, makes its stability be better than conventional liposome, and multivesicular liposome can be realized the reason of the slow controlled release of medicine, just is that also it has this particular structure.Through verification experimental verification: the compound sulfamonomethoxine sodium multivesicular liposome slow release effect is obvious, still has medicine evenly to discharge at 96h, and this has proved that multivesicular liposome can be than ordinary preparation, common single chamber, the more prolong drug of multilamelar liposome release time.
In this experiment after the blood specimen collection, sample segment sealed to be stored in 4 ℃ of refrigerators with 3 layers of preservative film measure behind the 24h, its result measures than centrifugalize immediately, drug level on average reduces about 10%, measure after preserving 48 h, it is about 17% that drug level reduces, and prompting is in the stored refrigerated process, and medicine has settled trend.Therefore, during conditions permit, should try one's best and in time handle sample.If can't in time handle because of sample size is many, in time separated plasma-20 is ℃ frozen to be measured.
According to document announcement, the sulfamonomethoxine sodium drug administration by injection meets two Room kinetic models; Oral administration meets a Room kinetic model.Drug-time curve after the compound sulfamonomethoxine sodium multivesicular liposome intramuscular injection is an one-compartment model, has reacted medicine after liposomal encapsulated, and obvious change has taken place medicine dynamic metabolism in animal body.According to another document announcement, the composition of liposome, particle diameter, electric charge, route of administration, dosage and administration frequency all influence the body internal dynamics of medicine.
Multivesicular liposome is because its particular structure, its release should be a slow process at the uniform velocity as can be known, the rabbit pharmacokinetics studies show that, the prominent phenomenon of releasing was arranged in one hour, reason may with the multivesicular liposome suspension in contain in some free medicines or the lipid fragment and contain some drug-induceds, so when using the multivesicular liposome suspension, need centrifugal supernatant to be gone out free drug.
Compound sulfamonomethoxine sodium multivesicular liposome is at the intravital biological half-life t of rabbit
1/2Be 51.5h, area AUC is 1049.70h.mg/L under the drug-time curve, and apparent volume of distribution is 1536.53mL/kg, and clearance rate is 19.05mL/d, still has two fun gi polysaccharides to occur behind administration 96h.According to another bibliographical information, sulfamonomethoxine sodium is at the intravital biological half-life t of rabbit
1/2Be 2.94h, area AUC is 537.7h. μ g/mL under the drug-time curve, after this shows that the composite sulfamonomethoxine sodium lipidosome is sealed, significant change has taken place in its pharmacokinetics and tissue distribution, drug metabolism speed slows down greatly, and the effective blood drug concentration time lengthening improves curative effect.
Claims (8)
1. compound sulfamonomethoxine sodium multivesicular liposome, it is characterized in that described multivesicular liposome is to comprise lipid: wrapped up hydrophilic medicament sulfamonomethoxine sodium and lipophilic drugs trimethoprim simultaneously in the multivesicular liposome structure that soybean lecithin, cholesterol and triacylglycerol form; Folliculus particle size range 10-40 μ m in the described multivesicular liposome; During synthetic described multivesicular liposome, the adding proportion of the gross mass of sulfamonomethoxine sodium and trimethoprim gross mass and lipid is 1: 4-1: 10; The interpolation mass ratio of sulfamonomethoxine sodium and trimethoprim is 10: 3-4: 1; The interpolation mass ratio of soybean lecithin and cholesterol is 1-4: 1; The consumption of triacylglycerol is 8-16/mmolL
-1
2. compound sulfamonomethoxine sodium multivesicular liposome according to claim 1 is characterized in that, during synthetic described multivesicular liposome, the adding proportion of the gross mass of sulfamonomethoxine sodium and trimethoprim gross mass and lipid is 1: 4; The interpolation mass ratio of sulfamonomethoxine sodium and trimethoprim is 4: 1; The interpolation mass ratio of soybean lecithin and cholesterol is 1: 1; The consumption of triacylglycerol is 16/mmolL
-1
3. the preparation method of the described compound sulfamonomethoxine sodium multivesicular liposome of claim 1 is characterized in that, may further comprise the steps:
(1) taking by weighing soybean lecithin, cholesterol, trimethoprim, triacylglycerol in proportion is dissolved in the 10-15mL chloroform and forms lipoprotein solution;
(2) sulfamonomethoxine sodium is dissolved in the 10-15mL ultra-pure water forms aqueous solution;
(3) with lipoprotein solution and aqueous solution, vortex vibration 1-10min, emulsifying 2-12min forms the w/o type colostrum on the ultrasonic cell-break machine then;
(4) get w/o type colostrum 5-10mL, add ultra-pure water 10-15mL, the 1-10min that on the vortex mixed instrument, vibrates, ultrasonic emulsification 2-5min; Form W/O/W type emulsion;
(5) get above-mentioned W/O/W type emulsion and on rotary evaporator, vapor away chloroform, promptly get compound sulfamonomethoxine sodium multivesicular liposome.
4. the preparation method of compound sulfamonomethoxine sodium multivesicular liposome according to claim 3 is characterized in that: also add Vit-E in the step (1) and be dissolved in the chloroform.
5. the preparation method of compound sulfamonomethoxine sodium multivesicular liposome according to claim 3, it is characterized in that: step (1) forms lipoprotein solution in 25-30 ℃ of water-bath.
6. the preparation method of compound sulfamonomethoxine sodium multivesicular liposome according to claim 3, it is characterized in that: step (3) is at emulsifying preincubation 2-5min.
7. the preparation method of compound sulfamonomethoxine sodium multivesicular liposome according to claim 3 is characterized in that: add Tween-80 and Span-80 again after adding ultra-pure water in the step (4), vibrate on the vortex mixed instrument.
8. the preparation method of compound sulfamonomethoxine sodium multivesicular liposome according to claim 3 is characterized in that: 45-50 ℃ of the middle rotary evaporation temperature of step (5), time 10-20min.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104434802A (en) * | 2014-12-09 | 2015-03-25 | 郑州后羿制药有限公司 | Compound sulfamonomethoxine lipidosome and preparation method thereof |
| CN107930503A (en) * | 2018-01-05 | 2018-04-20 | 苏州科技大学 | A kind of rotatable ultrasonic water disturbs device |
| CN109288796A (en) * | 2018-11-14 | 2019-02-01 | 天津市诺维动物药业有限公司 | Composite sulfamonomethoxine soluble powder of sodium |
| EP3590508A4 (en) * | 2017-03-02 | 2021-01-13 | Dandi Bioscience Inc | Multi-domain vesicle comprising immunoactive material, production method therefor and immunomodulatory composition comprising same |
| CN114948877A (en) * | 2022-05-30 | 2022-08-30 | 华裕(无锡)制药有限公司 | Ropivacaine hydrochloride liposome injection and preparation method thereof |
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| US5807572A (en) * | 1988-02-18 | 1998-09-15 | Depotech Corporation | Multivesicular liposomes having a biologically active substance encapsulated therein in the presence of a hydrochloride |
| CN101416936A (en) * | 2007-10-22 | 2009-04-29 | 洛阳普莱柯生物工程有限公司 | Preparation method of long-acting composite sulfamonomethoxine suspension |
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| US5807572A (en) * | 1988-02-18 | 1998-09-15 | Depotech Corporation | Multivesicular liposomes having a biologically active substance encapsulated therein in the presence of a hydrochloride |
| CN101416936A (en) * | 2007-10-22 | 2009-04-29 | 洛阳普莱柯生物工程有限公司 | Preparation method of long-acting composite sulfamonomethoxine suspension |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104434802A (en) * | 2014-12-09 | 2015-03-25 | 郑州后羿制药有限公司 | Compound sulfamonomethoxine lipidosome and preparation method thereof |
| EP3590508A4 (en) * | 2017-03-02 | 2021-01-13 | Dandi Bioscience Inc | Multi-domain vesicle comprising immunoactive material, production method therefor and immunomodulatory composition comprising same |
| CN107930503A (en) * | 2018-01-05 | 2018-04-20 | 苏州科技大学 | A kind of rotatable ultrasonic water disturbs device |
| CN107930503B (en) * | 2018-01-05 | 2023-08-11 | 苏州科技大学 | Rotatable ultrasonic wave water scrambler |
| CN109288796A (en) * | 2018-11-14 | 2019-02-01 | 天津市诺维动物药业有限公司 | Composite sulfamonomethoxine soluble powder of sodium |
| CN114948877A (en) * | 2022-05-30 | 2022-08-30 | 华裕(无锡)制药有限公司 | Ropivacaine hydrochloride liposome injection and preparation method thereof |
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