CN105560181A - Injectable slow-released nanoemulsion preparation prepared from mequindox and preparation method of preparation - Google Patents
Injectable slow-released nanoemulsion preparation prepared from mequindox and preparation method of preparation Download PDFInfo
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Abstract
The invention provides an injectable slow-released nanoemulsion preparation prepared from mequindox and a preparation method of the preparation. The injectable slow-released nanoemulsion preparation prepared from mequindox is mainly prepared from tween 80, span 80, isopropyl myristate, absolute ethyl alcohol, polyvinylpyrrolidone, mequindox and purified water and is an oil-in-water (O/W) type nanoemulsion preparation capable of being massively diluted, and the preparation is in nano-scaled size, high in drug loading capacity and stability, controllable in quality and capable of overcoming the defects of an existing injection and lipid emulsion and can be suitable for conventional injection modes such as hypodermic injection, intramuscular injection and intravenous injection. The preparation method of the injectable slow-released nanoemulsion preparation prepared from mequindox is simple in technology, an oil-in-water (O/W) method is adopted to prepare mequindox nano microspheres, the in-vivo release rate of the drug is delayed by modifying dosage forms of the drug, therefore, the half-life in vivo of the drug is prolonged, and the bioavailability of the drug is improved; by means of a filtration sterilization mode, effective sterilization can be conducted on the obtained nanoemulsion.
Description
Technical field
The present invention relates to Animal Medicine health care technology field, in particular to a kind of LIJUNJING injectable sustained-release nano-emulsion preparation and preparation method thereof.
Background technology
In line with international standards as early as possible to make the animal food of China produce for improving animal health medical level, developing the novel chiral synthon of broad-spectrum high-efficiency and low-toxicity, exploitation novel formulation and new medicine-feeding technology just becomes the important topic of pendulum in face of vast veterinary drug worker.Medicine needs to be suitable for medical treatment and prophylactic applications with certain dosage form, and whether clinical efficacy and the dosage form used of medicine rationally have direct relation.Exploitation novel form, improves conventional medicament with Modern New Technology new material, expands its purposes, more much lower than development novel chiral synthon expense and the cycle is short, and have higher economic rate of return, nano controlled-release preparation is the current dosage form being subject to common concern.
The one that nano-emulsion (Nanoemulsion) is nano controlled-release preparation, also microemulsion (Microemulsion) is claimed, particle diameter is between 10 ~ 100nm, be formed by proper proportion by oil phase, aqueous phase, surfactant and cosurfactant a kind of stable transparent, low-viscosity isotropy and thermodynamically stable dispersion, as long as the composition of four phases is suitable, can form homogeneous transparent or show slightly the liquid of opalescence, be thermodynamic stable system.Because nano-emulsion has outstanding targeting, slow releasing function and the solubilization powerful to insoluble drug, the research of nano-emulsion drug-supplying system is in recent years subject to the extensive concern of Chinese scholars always.In addition, nano-emulsion, as a kind of new drug carrier, is divided into different administering modes according to the characteristic of contained medicine and the dissimilar of Emulsion: transdermal administration, oral administration, mucosal drug delivery, drug administration by injection etc.Meanwhile, advanced nano-emulsion apparatus for preparation, EXPERIMENTAL DESIGN scheme, checkout equipment, computer software etc. are also for also just being developed further in the preparation of nano-emulsion.Nano-emulsion has the solubilization powerful to insoluble drug as a kind of new drug carrier system, also has the advantages such as obvious slow releasing function, targeting and higher bioavailability, has broad application prospects at art of pharmacy.
At present, although have some for clinical nano-emulsion, as: Sandoz Inc. is for Cyclosporine microemulsion precursor capsule preparations (SandimmunNeor), Contrafungin microemulsion and the CAPSOFT microemulsion being used for the treatment of psoriasis and neurodermatitis etc., but still face some problems.On the one hand, although have employed nonionic low toxicity surfactant in the preparation process of nano-emulsion, due to its consumption >=10% in system), still some toxic and side effects and anaphylaxis are produced to body, and conventional cosurfactant there is certain zest to body.Secondly, nano-emulsion will carry out autoclaving before encapsulation is preserved, and temperature has often exceeded the point (Cloudpoint) covered with clouds of surfactant, made Emulsion become muddiness even breakdown of emulsion and cause medicine to be separated out.Preserve in room temperature or low-temperature dark.In addition, will enter blood after the quiet note of nano-emulsion, and water-in-oil type (W/O) type nano-emulsion can not by Macrodilution, this will consider the problem that may cause thrombosis.
LIJUNJING (Maquindox) has another name called Mequindox, is the drug of first choice that treatment serious harm animal and bird intestines infects.The product of LIJUNJING mainly contains powder, pre-mixing agent, injection etc. clinically at present.Because its toxicity causes animal to this medical instrument for certain sensitivity, repeatedly occur owing to taking the improper event causing poultry poisoning on veterinary clinic in recent years, this medicine is for oral administration simultaneously easily absorbs, be distributed in whole body respectively to organize, disappear in body fast, blood halflife very short (T1/2 is 2h), limits its use clinically.
In view of this, special proposition the present invention.
Summary of the invention
The first object of the present invention is to provide a kind of LIJUNJING injectable sustained-release nano-emulsion preparation, described LIJUNJING injectable sustained-release nano-emulsion preparation is of a size of nanoscale, drug loading and stability high, quality controllable, there is sustained-release synergistic function, the shortcoming of existing injection and lipomul can be overcome, be applicable to the regular injection modes such as subcutaneous injection, intramuscular injection, intravenous injection.
The second object of the present invention is the preparation method providing a kind of described LIJUNJING injectable sustained-release nano-emulsion preparation, and the method technique is simple, is applicable to large-scale production.
In order to realize above-mentioned purpose of the present invention, spy by the following technical solutions:
A kind of LIJUNJING injectable sustained-release nano-emulsion preparation, prepares primarily of Tween 80, class 80 of department, isopropyl myristate, dehydrated alcohol, polyvinylpyrrolidone, LIJUNJING, purified water;
In every 1000mL LIJUNJING injectable sustained-release nano-emulsion preparation, the usage ratio of above-mentioned raw materials is Tween 80 60-180mL: department class 8012-36mL: isopropyl myristate 24-72mL: dehydrated alcohol 40-120mL: polyvinylpyrrolidone 2-6g: LIJUNJING 10-30g, surplus is purified water.
LIJUNJING injectable sustained-release nano-emulsion preparation of the present invention adopts specific composition composition and consumption, for a kind of can by the oil-in-water of Macrodilution (O/W) type nano-emulsion preparation, it is of a size of nanoscale, mean diameter is only 50nm, drug loading and stability high, quality controllable, the shortcoming of existing injection and lipomul can be overcome, be applicable to the regular injection modes such as subcutaneous injection, intramuscular injection, intravenous injection.
The more existing preparation of LIJUNJING injectable sustained-release nano-emulsion preparation of the present invention possesses obvious sustained-release synergistic function, tested and clinical trial by vitro release, LIJUNJING injectable sustained-release nano-emulsion preparation of the present invention more common LIJUNJING injection possesses better sustained release performance and therapeutic effect, gained LIJUNJING injectable sustained-release nano-emulsion preparation release in vitro rate of the present invention is original 3-4 times, times for spraying and dosage can be reduced, save medicine cost, reduce medicine residue of veterinary drug in animal body, can toxic and side effects be reduced.
LIJUNJING injectable sustained-release nano-emulsion preparation of the present invention adopts nano-emulsion as pharmaceutical carrier, can increase the dissolubility of poorly water soluble drugs; Medicine can be disperseed well, absorb rapidly, improve bioavailability.Some volatile medicines, after making nano-emulsion, can prevent oxidation of drug, hydrolysis etc., improve the stability of medicine, mask bad abnormal smells from the patient, reach the object etc. of slow release or target administration.
Preferably, in every 1000mL LIJUNJING injectable sustained-release nano-emulsion preparation, the usage ratio of above-mentioned raw materials is Tween 80 90-150mL: department class 8018-30mL: isopropyl myristate 36-60mL: dehydrated alcohol 60-100mL: polyvinylpyrrolidone 3-5g: LIJUNJING 15-25g, surplus is purified water.
Further preferably, in every 1000mL LIJUNJING injectable sustained-release nano-emulsion preparation, the usage ratio of above-mentioned raw materials is Tween 80 120mL: department class 8024mL: isopropyl myristate 48mL: dehydrated alcohol 80mL: polyvinylpyrrolidone 4g: LIJUNJING 20g, surplus is purified water.
Tween 80 and Si Ban 80 are nonionic surfactant and emulsifying agent respectively simultaneously, and wherein Tween 80 is soluble in water, is dissolved in ethanol, vegetable oil, ethyl acetate, methanol, toluene, is insoluble to mineral oil.Agglutination during low temperature, restores after being heated.And the class of department 80 is insoluble in water, be dissolved in deep fat and organic solvent.In addition, compare existing nonionic surfactant and emulsifying agent, the haemolysis of Tween 80 is extremely weak.
Isopropyl myristate is wetting agent and emulsifying agent, water insoluble, can with the immiscible organic solvents such as alcohol, ether, METHYLENE CHLORIDE, oils and fats; In addition, isopropyl myristate is a kind of nontoxic, non-irritating material.
Polyvinylpyrrolidone, as a kind of synthesizing water-solubility macromolecular compound, has the general aspects of water-soluble high-molecular compound, colloid protective effect, film property, caking property, hygroscopicity, solubilising or cohesion; In addition, also there is excellent solubility property and physiological compatibility.Polyvinylpyrrolidone has both water-soluble, is dissolved in again the bulk properties that majority of organic solvent, toxicity are very low, physiological compatibility is good.
Dehydrated alcohol can dissolve the raw material being insoluble in water, can also dissolve each other in addition with aqueous phase, promotes mutually to dissolve dispersion, reduces the granularity of gained nano-emulsion.
Purified water is injection medicament water, can adopt distilled water.
The preparation method of above-mentioned a kind of LIJUNJING injectable sustained-release nano-emulsion preparation, comprises the steps:
(1) take the Tween 80 of above-mentioned weight in proportion, department class 80, isopropyl myristate are mixed and obtain composite emulsifying liquid, take LIJUNJING in composite emulsifying liquid, continue heating for dissolving and obtain A liquid;
(2) taking polyvinylpyrrolidone adds in dehydrated alcohol, adds A liquid, as oil phase after preheating;
(3) purified water is measured as aqueous phase;
(4) be added drop-wise in oil phase by aqueous phase, drip while stir, solution becomes muddiness then by muddiness change clarification by clarifying, and namely obtains nano-emulsion;
(5) gained nano-emulsion is passed through membrane filtration, pass into noble gas embedding, high temperature sterilize, namely obtain a kind of LIJUNJING injectable sustained-release nano-emulsion preparation.
The preparation method technique of LIJUNJING injectable sustained-release nano-emulsion preparation of the present invention is simple, oil-in-water method (O/W) is adopted to prepare LIJUNJING Nano microsphere, this medicine rate of release is in vivo delayed by transformation pharmaceutical dosage form, thus extend the Half-life in vivo of this medicine, improve the bioavailability of this medicine; Adopt filtration sterilization mode, effective sterilizing can be carried out to gained nano-emulsion.
Preferably, in step (1), heating-up temperature is 20-80 DEG C, is preferably 40-60 DEG C, more preferably 55 DEG C.
Adopt specified temp, contribute to the dispersion effect that dissolves each other improving Tween 80, class 80 of department, isopropyl myristate and LIJUNJING.
Preferably, in step (2), preheat temperature is 20-80 DEG C, is preferably 40-60 DEG C, more preferably 55 DEG C.
Adopt specified temp, contribute to polyvinylpyrrolidone and fully dissolve dispersion in water.
Preferably, oil phase is placed in constant temperature blender with magnetic force in (4) by step, and aqueous phase is added dropwise in the oil phase being in constant temperature stirring under the drain of constant flow pump.
Preferably, the oil phase temperature of described constant temperature stirring is 20-80 DEG C, is preferably 40-60 DEG C, more preferably 55 DEG C.
At a certain temperature, in oil phase, drip aqueous phase, oil-in-water (O/W) type nano-emulsion preparation can be obtained, and promote that it disperses, reduce granularity.
Preferably, described in step (5), filter sizes is less than 1 μm, is preferably less than 0.5 μm, more preferably less than 0.2 μm.
Preferably, described noble gas is nitrogen.
Preferably, at 119-123 DEG C of sterilizing 10-20min in step (5), preferably at 120-122 DEG C of sterilizing 12-18min, preferred at 121 DEG C of sterilizing 15min further.
Adopt and filter and the mode of sterilizing at high temperature under high pressure, effectively can carry out sterilizing to gained nano-emulsion, obtain uniform and stable nano-emulsion, effectively prevent gained nano-emulsion from becoming muddiness even breakdown of emulsion and cause medicine to be separated out.
In preparation LIJUNJING injectable sustained-release nano-emulsion preparation process, poorly soluble due to LIJUNJING itself, this drug level directly affects stablizing of nano-emulsion, drug level is too low, do not reach desirable therapeutic effect, during excessive concentration, then nano-emulsion is easily separated out; Adopt ethanol equal solvent as the cosolvent of LIJUNJING, enable dissolve very well and not easily separate out at low temperatures, ethanol is also good co-emulsifier simultaneously.Temperature is also affect key factor prepared by nano-emulsion, when solution temperature is too high in oil for medicine, causes drug solution variable color and affects the state observation that nano-emulsion formed, when temperature is too low, then can not form nano-emulsion, only form gelatin thing.
LIJUNJING injectable sustained-release nano-emulsion preparation preparation technology of the present invention is simple, drug loading and stability high, quality controllable, overcome the shortcoming of existing injection and lipomul, and size controlling is at nanoscale, not only can be directly used in muscle and subcutaneous injection, also can be used for intravenous injection.
Compared with prior art, beneficial effect of the present invention is:
LIJUNJING injectable sustained-release nano-emulsion preparation of the present invention adopts specific composition composition and consumption, for a kind of can by the oil-in-water of Macrodilution (O/W) type nano-emulsion preparation, it is of a size of nanoscale, drug loading and stability high, quality controllable, the shortcoming of existing injection and lipomul can be overcome, be applicable to the regular injection modes such as subcutaneous injection, intramuscular injection, intravenous injection.
The more existing preparation of LIJUNJING injectable sustained-release nano-emulsion preparation of the present invention possesses obvious sustained-release synergistic function, tested and clinical trial by vitro release, LIJUNJING injectable sustained-release nano-emulsion preparation of the present invention more common LIJUNJING injection possesses better sustained release performance and therapeutic effect, gained LIJUNJING injectable sustained-release nano-emulsion preparation release in vitro rate of the present invention is original 3-4 times, times for spraying and dosage can be reduced, save medicine cost, reduce medicine residue of veterinary drug in animal body, can toxic and side effects be reduced.
LIJUNJING injectable sustained-release nano-emulsion preparation of the present invention adopts nano-emulsion as pharmaceutical carrier, can increase the dissolubility of poorly water soluble drugs; Medicine can be disperseed well, absorb rapidly, improve bioavailability.Some volatile medicines, after making nano-emulsion, can prevent oxidation of drug, hydrolysis etc., improve the stability of medicine, mask bad abnormal smells from the patient, reach the object etc. of slow release or target administration.
The preparation method technique of LIJUNJING injectable sustained-release nano-emulsion preparation of the present invention is simple, oil-in-water method (O/W) is adopted to prepare LIJUNJING Nano microsphere, this medicine rate of release is in vivo delayed by transformation pharmaceutical dosage form, thus extend the Half-life in vivo of this medicine, improve the bioavailability of this medicine; Adopt filtration sterilization mode, effective sterilizing can be carried out to gained nano-emulsion.
Accompanying drawing explanation
In order to be illustrated more clearly in the specific embodiment of the invention or technical scheme of the prior art, be briefly described to the accompanying drawing used required in detailed description of the invention or description of the prior art below, apparently, accompanying drawing in the following describes is some embodiments of the present invention, for those of ordinary skill in the art, under the prerequisite not paying creative work, other accompanying drawing can also be obtained according to these accompanying drawings.
Fig. 1 is the transmission electron microscope photo of the embodiment of the present invention 5 gained LIJUNJING injectable sustained-release nano-emulsion preparation;
Fig. 2 is the grain size distribution of the embodiment of the present invention 5 gained LIJUNJING injectable sustained-release nano-emulsion preparation;
Fig. 3 is the vitro release curve comparison figure of the embodiment of the present invention 5 gained LIJUNJING injectable sustained-release nano-emulsion preparation; Wherein, y1 is the vitro release curve of LIJUNJING in normal injection, and y2 is the vitro release curve of the embodiment of the present invention 5 gained LIJUNJING injectable sustained-release nano-emulsion preparation.
Detailed description of the invention
Below in conjunction with the drawings and specific embodiments, technical scheme of the present invention is clearly and completely described, but it will be understood to those of skill in the art that, following described embodiment is the present invention's part embodiment, instead of whole embodiments, only for illustration of the present invention, and should not be considered as limiting the scope of the invention.Based on the embodiment in the present invention, those of ordinary skill in the art, not making the every other embodiment obtained under creative work prerequisite, belong to the scope of protection of the invention.Unreceipted actual conditions person in embodiment, the condition of conveniently conditioned disjunction manufacturer suggestion is carried out.Agents useful for same or the unreceipted production firm person of instrument, be and can buy by commercially available the conventional products obtained.
The specific embodiment of the invention provides the preparation method of some LIJUNJING injectable sustained-release nano-emulsion preparations.Related experiment material is as follows:
1. experimental facilities:
78HW-1 type constant temperature blender with magnetic force (Hangzhou motor for instrument factory); Constant flow pump (Shanghai Hu Xi analytical tool Co., Ltd., Factory); Transmission electron microscope (Hunan Institute of Analysis of agricultural university); Precision electronic analytical balance (AUW120D, ShimadzuCorporationJapan); General-purpose electric oven (Beijing is bright Medical Instruments factory forever); Constant temperature humidity chamber (Chongqing Sida Test Equipment Co., Ltd.); Acidometer (PHS-3C, magnetic electronic Science and Technology Ltd. is got in Shanghai); Ultraviolet-uisible spectrophotometer (GoldS53, Shanghai Hua Yan instrument and equipment company limited).
2. reagent:
Isopropyl myristate (chemical pure, Chemical Reagent Co., Ltd., Sinopharm Group); Tween 80 (tween80, AR, Tianjin great Mao chemical reagent factory); Class 80 of department (span80), dehydrated alcohol (AR, Chemical Reagent Co., Ltd., Sinopharm Group); PVP K30 (Boai Xinkaiyuan Pharmacy stock Co., Ltd); PBS (PH=7.0); LIJUNJING (injection stage, Zhong Mu Anda, Hubei pharmaceutcal corporation, Ltd); Methanol, dimethyl formamide (AR, Tianjin great Mao chemical reagent company limited); Hydrochloric acid (AR, Teng Longyuan Industrial Co., Ltd. of Shenzhen).
Embodiment 1
A preparation method for LIJUNJING injectable sustained-release nano-emulsion preparation, comprises the steps:
(1) take 60mL Tween 80, class of 12mL department 80,24mL isopropyl myristate be mixed and obtain composite emulsifying liquid, take 10g LIJUNJING in composite emulsifying liquid, continue to be heated to 20 DEG C, dissolve and obtain A liquid;
(2) take 2g PVP K30 to add in 40mL dehydrated alcohol, after being heated to 20 DEG C, add A liquid, as oil phase;
(3) measure purified water and be about 880mL (oil phase and the rear total amount of aqueous phase mixing are 1000mL) as aqueous phase;
(4) be placed in by oil phase in 18-22 DEG C of constant temperature blender with magnetic force, aqueous phase is added dropwise in the oil phase being in constant temperature stirring under the drain of constant flow pump, drop to solution and become muddy by clarifying, then it is bright to fade to clarification by muddiness, obtains nano-emulsion;
(5) by gained nano-emulsion by aperture be the membrane filtration of 1 μm, pass into nitrogen embedding, at 119 DEG C of autoclave sterilization 20min, namely obtain a kind of LIJUNJING injectable sustained-release nano-emulsion preparation.
Embodiment 2
A preparation method for LIJUNJING injectable sustained-release nano-emulsion preparation, comprises the steps:
(1) take 180mL Tween 80, class of 36mL department 80,72mL isopropyl myristate be mixed and obtain composite emulsifying liquid, take 30g LIJUNJING in composite emulsifying liquid, continue to be heated to 80 DEG C, dissolve and obtain A liquid;
(2) take 6g PVP K30 to add in 120mL dehydrated alcohol, be heated to 80 DEG C, add A liquid, as oil phase;
(3) measure purified water and be about 660mL (oil phase and the rear total amount of aqueous phase mixing are 1000mL) as aqueous phase;
(4) be placed in by oil phase in 78-82 DEG C of constant temperature blender with magnetic force, aqueous phase is added dropwise in the oil phase being in constant temperature stirring under the drain of constant flow pump, drop to solution and become muddy by clarifying, then it is bright to fade to clarification by muddiness, obtains nano-emulsion;
(5) by gained nano-emulsion by aperture be the membrane filtration of 0.5 μm, pass into nitrogen embedding, at 123 DEG C of autoclave sterilization 10min, namely obtain a kind of LIJUNJING injectable sustained-release nano-emulsion preparation.
Embodiment 3
A preparation method for LIJUNJING injectable sustained-release nano-emulsion preparation, comprises the steps:
(1) take 90mL Tween 80, class of 18mL department 80,36mL isopropyl myristate be mixed and obtain composite emulsifying liquid, take 15g LIJUNJING in composite emulsifying liquid, continue to be heated to 40 DEG C, dissolve and obtain A liquid;
(2) take 3g PVP K30 to add in 60mL dehydrated alcohol, be heated to 40 DEG C, add A liquid, as oil phase;
(3) measure purified water and be about 820mL (oil phase and the rear total amount of aqueous phase mixing are 1000mL) as aqueous phase;
(4) be placed in by oil phase in 38-42 DEG C of constant temperature blender with magnetic force, aqueous phase is added dropwise in the oil phase being in constant temperature stirring under the drain of constant flow pump, drop to solution and become muddy by clarifying, then it is bright to fade to clarification by muddiness, obtains nano-emulsion;
(5) by gained nano-emulsion by aperture be the membrane filtration of 0.4 μm, pass into nitrogen embedding, at 120 DEG C of autoclave sterilization 18min, namely obtain a kind of LIJUNJING injectable sustained-release nano-emulsion preparation.
Embodiment 4
A preparation method for LIJUNJING injectable sustained-release nano-emulsion preparation, comprises the steps:
(1) take 150mL Tween 80, class of 30mL department 80,60mL isopropyl myristate be mixed and obtain composite emulsifying liquid, take 25g LIJUNJING in composite emulsifying liquid, continue to be heated to 60 DEG C, dissolve and obtain A liquid;
(2) take 5g PVP K30 to add in 100mL dehydrated alcohol, after being heated to 60 DEG C, add A liquid, as oil phase;
(3) measure purified water and be about 680mL (oil phase and the rear total amount of aqueous phase mixing are 1000mL) as aqueous phase;
(4) be placed in by oil phase in 58-62 DEG C of constant temperature blender with magnetic force, aqueous phase is added dropwise in the oil phase being in constant temperature stirring under the drain of constant flow pump, drop to solution and become muddy by clarifying, then it is bright to fade to clarification by muddiness, obtains nano-emulsion;
(5) by gained nano-emulsion by aperture be the membrane filtration of 0.3 μm, pass into nitrogen embedding, at 122 DEG C of autoclave sterilization 12min, namely obtain a kind of LIJUNJING injectable sustained-release nano-emulsion preparation.
Embodiment 5
A preparation method for LIJUNJING injectable sustained-release nano-emulsion preparation, comprises the steps:
(1) take 120mL Tween 80, class of 24mL department 80,48mL isopropyl myristate be mixed and obtain composite emulsifying liquid, take 20g LIJUNJING in composite emulsifying liquid, continue to be heated to 55 DEG C, dissolve and obtain A liquid;
(2) take 4g PVP K30 to add in 80mL dehydrated alcohol, after being heated to 55 DEG C, add A liquid, as oil phase;
(3) measure purified water and be about 750mL (oil phase and the rear total amount of aqueous phase mixing are 1000mL) as aqueous phase;
(4) be placed in by oil phase in 53-57 DEG C of constant temperature blender with magnetic force, aqueous phase is added dropwise in the oil phase being in constant temperature stirring under the drain of constant flow pump, dropping to solution bright to clarifying, obtaining nano-emulsion;
(5) by gained nano-emulsion by aperture be the membrane filtration of 0.2 μm, pass into nitrogen embedding, at 121 DEG C of autoclave sterilization 15min, namely obtain a kind of LIJUNJING injectable sustained-release nano-emulsion preparation.
Experimental example 1
1. nano-emulsion discrimination test:
Adopt the centrifugal 10min of 2000r/min, observing as being homogeneous yellow clear liquid and possessing dindar optical phenomena, is then nano-emulsion.Made nano-emulsion small beaker is divided into two parts and instills tonyred dye liquor and each two of methylene blue dye liquor respectively, observe the diffusion velocity of dye liquor in nano-emulsion.If the diffusion velocity of methylene blue dye liquor in nano-emulsion is faster than tonyred dye liquor, is oil-in-water type nano-emulsion (O/W), otherwise is then water-in-oil type nanoemulsion (W/O).
2. nano-emulsion morphologic observation and grain diameter measurement:
Get LIJUNJING nano-emulsion quantitative, drip after dilution and be applied to copper mesh on a small quantity, under transmission electron microscope, observe its fractions distribution after drying, and complete nano-emulsion grain diameter measurement under transmission electron microscope.
3. assay:
(1) selection of wavelength is measured:
LIJUNJING reference substance is appropriate, adds dimethyl formamide 10mL, and 0.1mol/L hydrochloric acid solution 30mL adds methanol after dissolving and is made into 10 μ g/mL solution, take methanol as blank, in the interscan of 200 ~ 400nm wave-length coverage, record absorption spectrum, finds there is absorption maximum at 380nm wavelength place.Getting LIJUNJING solvent for use to detect, at this wavelength without absorption, therefore adopting 380nm for measuring wavelength.
(2) mensuration of reference substance solution trap (standard curve):
Precision takes LIJUNJING reference substance 50mg, put in the brown measuring bottle of 250mL, add dimethyl formamide 10mL, hydrochloric acid solution (0.1mol/L) 30mL, jolting makes dissolving, add water to scale, shake up, respectively precision measure 0.5,1,2,3,5,10mL, put in the brown volumetric flask of 100mL, with methanol dilution to scale, shake up.Take methanol as blank, measure trap at 380nm wavelength place.
(3) nano-emulsion assay:
Precision measures LIJUNJING nano-emulsion 2mL, puts in the brown volumetric flask of 250mL, adds dimethyl formamide 10mL, hydrochloric acid solution (0.1mol/mL) 30mL.Shake up, add water to scale, shake up, precision measures 5mL, puts in the brown measuring bottle of 100mL, with methanol dilution to scale, shakes up, and according to spectrophotography, measures at 380nm wavelength place.
(4) nano-emulsion preparation accelerated stability is investigated:
Regulation according to " veterinary drug stability test technical specification " Chinese medicine accelerated test carries out stability test.Three batches of injection LIJUNJING nanoemulsions are placed in 30 DEG C, relative humidity is the climatic chamber of 65%, regularly take out sample, investigate the outward appearance of nano-emulsion, particle diameter, pH value and medicament contg changing condition.
Experimental result
1. the trap of reference substance solution and regression equation:
Concrete outcome is in table 1.The regression equation of trap (y) to concentration (x, μ g/mL) is: y=0.055x+0.0091, R2=0.999.Result of the test shows, in 1-20 μ g/mL concentration range, trap and concentration are good linear relationship.
The trap concentration of table 1 reference substance solution
2. gained LIJUNJING injectable sustained-release nano-emulsion preparation property determination of the present invention:
Result is as shown in table 2.Can find out, gained LIJUNJING injectable sustained-release nano-emulsion preparation transparency of the present invention is high, and medicament contg is high, and particle diameter is little, and in stable condition.
Table 2 gained LIJUNJING of the present invention injectable sustained-release nano-emulsion preparation performance data
3. gained LIJUNJING injectable sustained-release nano-emulsion preparation discrimination test of the present invention:
Result is gained LIJUNJING injectable sustained-release nano-emulsion preparation (embodiment 1-embodiment 5) of the present invention is homogeneous yellow clear liquid, and possesses dindar optical phenomena, is nano-emulsion.Diffusion experiment result be the diffusion velocity of methylene blue dye liquor in gained LIJUNJING injectable sustained-release nano-emulsion preparation (embodiment 1-embodiment 5) of the present invention faster than tonyred dye liquor, be oil-in-water type nano-emulsion (O/W).
4. the injectable sustained-release nano-emulsion preparation morphologic observation of the embodiment of the present invention 5 gained LIJUNJING and particle size determination:
Result as depicted in figs. 1 and 2.Can find out that the embodiment of the present invention 5 gained LIJUNJING injectable sustained-release nano-emulsion preparation particle is comparatively regular spherical, be evenly distributed, mean diameter is 50nm.
5. the accelerated stability test of the embodiment of the present invention 5 gained LIJUNJING injectable sustained-release nano-emulsion preparation:
Result is as shown in table 3.The embodiment of the present invention 5 gained LIJUNJING injectable sustained-release nano-emulsion preparation good stability, each index all meets the requirements.
Table 3 embodiment of the present invention 5 gained LIJUNJING injectable sustained-release nano-emulsion preparation stability test result (x ± s, n=3)
Experimental example 2
The embodiment of the present invention 5 gained LIJUNJING injectable sustained-release nano-emulsion preparation vitro release is tested:
(1) material: six glasss of drug dissolution instrument (Wuhan Ace pendant scientific instrument company limited), LIJUNJING injection (Sichuan Qian Xing animal pharmaceutical estate company limited), the embodiment of the present invention 5 gained LIJUNJING injectable sustained-release nano-emulsion preparation (laboratory self-control), ultraviolet-uisible spectrophotometer (GoldS53, Shanghai Hua Yan instrument and equipment company limited).
(2) method:
Measure the selection of wavelength and the selection of mensuration with reference to the mensuration wavelength in above-mentioned assay of reference substance solution trap (standard curve) and the mensuration of reference substance solution trap.
Drug release determination method: accurate measuring equivalent (by LIJUNJING cubage) LIJUNJING nano-emulsion, LIJUNJING normal injection are placed in bag filter respectively, bag filter is placed in hanging basket, and hanging basket puts into the stripping rotor that 350mL release medium (PBS) is housed; By dissolution instrument control built in (37 ± 0.5) DEG C, run under 100r/min condition, timing syringe samples 3.5mL from cup, and supplies release medium simultaneously.Sample PBS is diluted to 7mL, through membrane filtration after high speed centrifugation, under ultraviolet spectrophotometer, measures absorbance, and using formula calculates its cumulative release percentage rate.
Cumulative release percentage rate=(C
n× extension rate+∑ C
n-1× 3.5)/G × 100%
In formula, C
nrepresent the drug level in the release medium of every sub-sampling;
C
n-1drug level in the release medium of primary sample before representing;
G is the content of nanoparticle Chinese medicine; G=nanoparticle quality × drug loading.
Experimental result:
The embodiment of the present invention 5 gained LIJUNJING injectable sustained-release nano-emulsion preparation vitro release experimental result as shown in Figure 3, comparatively normal injection release profiles is steady for the embodiment of the present invention 5 gained LIJUNJING injectable sustained-release nano-emulsion preparation release profiles, in vitro after 80h discharge 70%, and common LIJUNJING injection in vitro 40h release rate close to 100%.Therefore the embodiment of the present invention 5 gained LIJUNJING injectable sustained-release nano-emulsion preparation more common LIJUNJING injection possesses obvious slow-release function.
Gained LIJUNJING injectable sustained-release nano-emulsion preparation of the present invention adopts oil-in-water emulsified legal system standby, and medicine is then wrapped in microsphere, and this makes the release of medicine need the skim first broken through outside microsphere, thus serve and delay to discharge pharmic function.
Experimental example 3
The embodiment of the present invention 5 gained LIJUNJING injectable sustained-release nano-emulsion preparation is to the Clinical Treatment Test of yellow and white dysentery of piglet:
(1) material:
Reagent and medicine: LIJUNJING injection (Sichuan Qian Xing animal pharmaceutical estate company limited), the embodiment of the present invention 5 gained LIJUNJING injectable sustained-release nano-emulsion preparation (laboratory self-control), syringe (No. 9 syringe needles);
Animal: select the piglet 80 suffering from HUANGBAI(sic) dysentery, piglet derives from Hunan Province's large―scale hoggery.Its diagnostic criteria is as follows:
Symptom: sick piglet spirit is depressed, thirsty, is reluctant to suck the breast, arranges yellow lark water sample loose stool and include curdled milk small pieces and bubble, or milk ejection white, canescence pulpous state or pasty state loose stool, and stench, spirit is depressed, sucks the breast and reduces, become thin, dehydration.
(2) method:
Curative effect determinate standard:
Recovery from illness: sick pig clinical symptom disappearance after medication, spirit is normal, and defecation is normal, and appetite is recovered.
Take a turn for the better: clinical symptoms starts to disappear, feces gradually retrogradation is extremely normal.
Invalid: clinical symptoms is not improved or produced drug resistance to said preparation due to pathogenic bacteria, and the state of an illness is on the rise, and continues to have loose bowels to serious dehydration.
Total effective rate=recovery from illness+improvement.
EXPERIMENTAL DESIGN:
The piglet suffering from HUANGBAI(sic) dysentery (cause of disease is escherichia coli) is divided into 2 groups at random, wherein test group 40, matched group 40.The test group piglet intramuscular injection embodiment of the present invention 5 gained LIJUNJING injectable sustained-release nano-emulsion preparation, once-a-day, is used in conjunction three days.Matched group injects common LIJUNJING injection.One day twice, be used in conjunction three days.
Experimental result:
Table 4 Clinical Treatment Test different disposal group clinical efficacy
As seen from Table 4, the total effective rate of test group to the treatment of HUANGBAI(sic) dysentery piglet reaches 97.5%, the treatment total effective rate of matched group to yellow and white dysentery of piglet is 90.0%, while the artificial administration number of times of minimizing and dosage, the effect of the embodiment of the present invention 5 gained LIJUNJING injectable sustained-release nano-emulsion preparation is also better than common LIJUNJING injection.As can be seen here, the embodiment of the present invention 5 gained LIJUNJING injectable sustained-release nano-emulsion preparation more common LIJUNJING injection possesses obvious slow release and synergistic effect.
Although illustrate and describe the present invention with specific embodiment, however it will be appreciated that can to make when not deviating from the spirit and scope of the present invention many other change and amendment.Therefore, this means to comprise all such changes and modifications belonged in the scope of the invention in the following claims.
Claims (10)
1. a LIJUNJING injectable sustained-release nano-emulsion preparation, is characterized in that, prepares primarily of Tween 80, class 80 of department, isopropyl myristate, dehydrated alcohol, polyvinylpyrrolidone, LIJUNJING, purified water;
In every 1000mL LIJUNJING injectable sustained-release nano-emulsion preparation, the usage ratio of above-mentioned raw materials is Tween 80 60-180mL: department class 8012-36mL: isopropyl myristate 24-72mL: dehydrated alcohol 40-120mL: polyvinylpyrrolidone 2-6g: LIJUNJING 10-30g, surplus is purified water.
2. a kind of LIJUNJING injectable sustained-release nano-emulsion preparation according to claim 1, it is characterized in that, in every 1000mL LIJUNJING injectable sustained-release nano-emulsion preparation, the usage ratio of above-mentioned raw materials is Tween 80 90-150mL: department class 8018-30mL: isopropyl myristate 36-60mL: dehydrated alcohol 60-100mL: polyvinylpyrrolidone 3-5g: LIJUNJING 15-25g, surplus is purified water.
3. a kind of LIJUNJING injectable sustained-release nano-emulsion preparation according to claim 2, it is characterized in that, in every 1000mL LIJUNJING injectable sustained-release nano-emulsion preparation, the usage ratio of above-mentioned raw materials is Tween 80 120mL: department class 8024mL: isopropyl myristate 48mL: dehydrated alcohol 80mL: polyvinylpyrrolidone 4g: LIJUNJING 20g, surplus is purified water.
4. the preparation method of a kind of LIJUNJING injectable sustained-release nano-emulsion preparation as described in as arbitrary in claim 1-3, is characterized in that, comprise the steps:
(1) take the Tween 80 of above-mentioned weight in proportion, department class 80, isopropyl myristate are mixed and obtain composite emulsifying liquid, take LIJUNJING in composite emulsifying liquid, continue heating for dissolving and obtain A liquid;
(2) taking polyvinylpyrrolidone adds in dehydrated alcohol, adds A liquid, as oil phase after preheating;
(3) purified water is measured as aqueous phase;
(4) be added drop-wise in oil phase by aqueous phase, drip while stir, solution becomes muddiness then by muddiness change clarification by clarifying, and namely obtains nano-emulsion;
(5) gained nano-emulsion is passed through membrane filtration, logical noble gas embedding, high temperature sterilize, namely obtains a kind of LIJUNJING injectable sustained-release nano-emulsion preparation.
5. the preparation method of a kind of LIJUNJING injectable sustained-release nano-emulsion preparation according to claim 1, is characterized in that, in step (1), heating-up temperature is 20-80 DEG C, is preferably 40-60 DEG C, more preferably 55 DEG C.
6. the preparation method of a kind of LIJUNJING injectable sustained-release nano-emulsion preparation according to claim 1, is characterized in that, in step (2), preheat temperature is 20-80 DEG C, is preferably 40-60 DEG C, more preferably 55 DEG C.
7. the preparation method of a kind of LIJUNJING injectable sustained-release nano-emulsion preparation according to claim 1, it is characterized in that, oil phase is placed in constant temperature blender with magnetic force in (4) by step, and aqueous phase is added dropwise in the oil phase being in constant temperature stirring under the drain of constant flow pump.
8. the preparation method of a kind of LIJUNJING injectable sustained-release nano-emulsion preparation according to claim 7, is characterized in that, the oil phase temperature of described constant temperature stirring is 20-80 DEG C, is preferably 40-60 DEG C, more preferably 55 DEG C.
9. the preparation method of a kind of LIJUNJING injectable sustained-release nano-emulsion preparation according to claim 1, it is characterized in that, described in step (5), filter sizes is less than 1 μm, is preferably less than 0.5 μm, more preferably less than 0.2 μm.
10. the preparation method of a kind of LIJUNJING injectable sustained-release nano-emulsion preparation according to claim 1, it is characterized in that, at 119-123 DEG C of sterilizing 10-20min in step (5), preferably at 120-122 DEG C of sterilizing 12-18min, preferred at 121 DEG C of sterilizing 15min further.
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| CN106727312A (en) * | 2016-12-30 | 2017-05-31 | 河南牧翔动物药业有限公司 | A kind of oil-in-water type quinoxaline nano-emulsion and preparation method thereof |
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