CN104055737A - Valnemulin hydrochloride microspheres and preparation method thereof - Google Patents
Valnemulin hydrochloride microspheres and preparation method thereof Download PDFInfo
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- CN104055737A CN104055737A CN201410038621.9A CN201410038621A CN104055737A CN 104055737 A CN104055737 A CN 104055737A CN 201410038621 A CN201410038621 A CN 201410038621A CN 104055737 A CN104055737 A CN 104055737A
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- valnemulin hydrochloride
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Abstract
The invention relates to valnemulin hydrochloride microspheres and preparation method thereof. The valnemulin hydrochloride microspheres are composed of a water phase, an oil phase and a crosslinking agent, wherein a volume ration of the water phase to the oil phase is 1:6-12. The water phase is composed of gelatin, valnemulin hydrochloride, polyvinylpyrrolidone and purified water and the oil phase is composed of an emulsifier and liquid paraffin. The preparation method includes following steps: preparing the water phase and the oil phase, adding the water phase dropwisely to the oil phase, adding the crosslinking agent, washing off the liquid paraffin on surfaces of the microspheres through petroleum ether and performing a vacuum-drying process to obtain the valnemulin hydrochloride microspheres.
Description
technical field
The present invention relates to a kind of valnemulin hydrochloride microsphere and preparation method thereof.
background technology
Valnemulin hydrochloride (Valnemulin Hydrochloride, VAL) be animal specific pleuromutilin analog derivative, this medicine has a broad antifungal spectrum, antibacterial activity is strong, to sensitivities such as antibacterial, Mycoplasma genus and spirillums, streptococcus, Actinobacillus, pasteurellosis bacillus, arthritis Mycoplasma, Nasus Bovis seu Bubali Mycoplasma, chicken septic Mycoplasma, mycoplasma pneumonia, Treponema Hyodysenteriae and colon pili sample spirillum etc. are all had to good antibacterial activity.The disease of external approved for preventing and treating pig, cattle, sheep.But valnemulin hydrochloride bitter in the mouth, hygroscopicity is extremely strong, and zest is large, and stability is relatively poor, is difficult for preserving, and absorbs rapidly in vivo, and the half-life is shorter, widely distributed.At present, home and abroad only has a kind of dosage form of valnemulin hydrochloride premix, because Clinical Dosage Form is single, has limited application and the popularization of this medicine.
Lung-targeted microspheres drug-supplying system refers to medicine dispersion or is adsorbed on the microsphere dispersion forming in macromolecular compound, polymer carrier materials, after administration, pastille microgranule is recycled to while reaching pulmonary through blood, can be distributed on the reticuloendothelial system phagocytic of lung tissue or be absorbed by pulmonary's blood capillary mechanicalness, can make medicine concentrate in lung tissue, thereby increase pulmonary's blood drug level, improve curative effect of medication, and systemic drug concentration reduces, toxic and side effects reduces.The problems such as that in addition, lung-targeted microspheres drug-supplying system can also solve that traditional non-targeted administration exists is less such as dissolubility, poor stability or malabsorption, the half-life is short, distribution is wide, therapeutic index is little.
summary of the invention
The object of the present invention is to provide a kind of new valnemulin hydrochloride preparation, i.e. valnemulin hydrochloride microsphere;
Another object of the present invention is to provide a kind of preparation method of valnemulin hydrochloride microsphere.
The object of the present invention is achieved like this:
A kind of valnemulin hydrochloride microsphere, is made up of water, oil phase and cross-linking agent, and wherein the volume ratio of water and oil phase is 1:6-12;
Described water is composed of the following components: gelatin, valnemulin hydrochloride, polyvinylpyrrolidone and purified water, wherein the bulking value specific concentration of gelatin is 7.5-15%, the bulking value specific concentration of valnemulin hydrochloride is 5-20%, and the weight ratio of polyvinylpyrrolidone and valnemulin hydrochloride is 0.5-3:1;
Described oil phase is made up of emulsifying agent and liquid paraffin, and wherein the volume of emulsifying agent is the 1-2.5% of oil phase volume;
Described cross-linking agent is glutaraldehyde, and its volume is the 3-7.5% of water and oil phase cumulative volume.
Described polyvinylpyrrolidone be selected from one in PVP k10, polyvinylpyrrolidone k25, polyvinylpyrrolidone k30 or polyvinylpyrrolidone k50, two or more.
Described emulsifying agent is class of department 80.
The preparation method of described a kind of valnemulin hydrochloride microsphere, preparation process is:
(a) by valnemulin hydrochloride micronization, and cross 100-300 mesh sieve, the gelatin that takes recipe quantity is put in beaker, add appropriate purified water fully swelling, after water bath with thermostatic control, then add micronization valnemulin hydrochloride and the polyvinylpyrrolidone of recipe quantity, stir and obtain water;
(b) measure class of department 80 and the liquid paraffin of recipe quantity, put in beaker and stir on electric heating magnetic stirring apparatus, obtain oil phase;
(c) water is added drop-wise in oil phase, electric heating magnetic agitation 15-20min, makes colostrum, put into rapidly ice-water bath, temperature is down to 4 DEG C of following continuation emulsifyings and is obtained emulsification system, adds 25% glutaraldehyde chemical cross-linking agent with thread, stir crosslinking curing, with isopropanol dehydration, washing, sucking filtration;
(d) wash the liquid paraffin of microsphere surface off with petroleum ether, vacuum drying 24h, the sterilizing of Co 60 x ray irradiation x, obtains valnemulin hydrochloride lung-targeted microspheres.
In described step (a), the temperature of water bath with thermostatic control is 50-70 DEG C.
In described step (b), the temperature of electric heating magnetic stirrer is 50-70 DEG C.
The mixing speed of the stirring crosslinking curing in described step (b) and step (c) in mixing speed and the step (c) of electric heating magnetic agitation is 600-1200rmin
-1.
technical scheme of the present invention has following advantages:
(1) valnemulin hydrochloride lung-targeted microspheres of the present invention, can reduce the zest of valnemulin hydrochloride, makes medicine slow release in animal body, extends action time, reduces the treatment number of times in clinical.
(2) valnemulin hydrochloride lung-targeted microspheres of the present invention, has high lung targeted characteristic, can improve pulmonary drug concentration, strengthens the sterilizing power of medicine, thereby medicament curative effect enhancement improves clinical therapeutic efficacy.
(3) valnemulin hydrochloride lung-targeted microspheres of the present invention, drug loading and envelop rate are high, have good stability, can improve the therapeutic effect of medicine.
(4) preparation technology of the present invention is simple, and production cost is low, is easy to realize industrialization, easy to use.
Brief description of the drawings
Fig. 1 valnemulin hydrochloride lung-targeted microspheres particle size distribution figure
The vitro release lab diagram of Fig. 2 valnemulin hydrochloride lung-targeted microspheres.
Detailed description of the invention
Form is by the following examples described in further detail foregoing of the present invention again, but this should be interpreted as to the scope of the above-mentioned theme of the present invention only limits to following example, all technology realizing based on foregoing of the present invention all belong to scope of the present invention
.
embodiment 1 acid hydrochloride salt valnemulin microsphere preparation example 1
Taking gelatin 2g puts in beaker, add 20mL ultra-pure water, complete swelling in 60 DEG C of water-baths, add again 1g micronization valnemulin hydrochloride (100-300 order) and 0.5g PVP, mix dissolving, then splashing in the container that fills 3.6mL department class 80 and 180mL liquid paraffin, is 900rmin at 55 DEG C, mixing speed
-1electromagnetic agitation 20min, makes colostrum, puts into rapidly ice-water bath temperature and is down to 4 DEG C of following stirring and emulsifying emulsifying 10min that continue, and adds 10mL25% glutaraldehyde chemical cross-linking agent with thread, stirs crosslinking curing 1h, with isopropanol dehydration, washing, sucking filtration; Wash again the liquid paraffin of microsphere surface off with a small amount of petroleum ether, vacuum drying 24h, the sterilizing of Co 60 x ray irradiation x, obtains faint yellow valnemulin hydrochloride lung-targeted microspheres.
By observation by light microscope microsphere shape, measure particle diameter, its content of high effective liquid chromatography for measuring with laser particle size analyzer.Result valnemulin hydrochloride gelatine microsphere mode of appearance rounding, good dispersion, mean diameter is 11.85 μ m, particle size distribution accounts for 91.7% of sum at the microsphere of 7～30 μ m.Microsphere drug loading is 17.32 ± 2.18%, and envelop rate is 84.51 ± 1.48%.
embodiment 2 acid hydrochloride salt valnemulin microsphere preparation examples 2
Taking gelatin 3g puts in beaker, add 40mL ultra-pure water, complete swelling in 60 DEG C of water-baths, add again 4g micronization valnemulin hydrochloride (100-300 order) and 4g PVP, mix dissolving, then splashing in the container that fills 2.4mL department class 80 and 240mL liquid paraffin, is 1000rmin at 60 DEG C, mixing speed
-1electromagnetic agitation 20min, makes colostrum, puts into rapidly ice-water bath temperature and is down to 4 DEG C of following stirring and emulsifying emulsifying 10min that continue, and adds 14mL25% glutaraldehyde chemical cross-linking agent with thread, stirs crosslinking curing 1h, with isopropanol dehydration, washing, sucking filtration; Wash again the liquid paraffin of microsphere surface off with a small amount of petroleum ether, vacuum drying 24h, the sterilizing of Co 60 x ray irradiation x, obtains faint yellow valnemulin hydrochloride lung-targeted microspheres.
By observation by light microscope microsphere shape, measure particle diameter, its content of high effective liquid chromatography for measuring with laser particle size analyzer.Result valnemulin hydrochloride gelatine microsphere mode of appearance rounding, good dispersion, mean diameter is 12.49 μ m, particle size distribution accounts for 90.8% of sum at the microsphere of 7～30 μ m.Microsphere drug loading is 19.35 ± 2.18%, and envelop rate is 91.52 ± 1.45%.
embodiment 3 acid hydrochloride salt valnemulin microsphere preparation examples 3
Taking gelatin 3g puts in beaker, add 20mL ultra-pure water, complete swelling in 60 DEG C of water-baths, add again 3g micronization valnemulin hydrochloride (100-300 order) and 4.5g PVP to mix dissolving, then splashing in the container that fills 6mL department class 80 and 240mL liquid paraffin, is 800rmin at 60 DEG C, mixing speed
-1electromagnetic agitation 20min, makes colostrum, puts into rapidly ice-water bath temperature and is down to 4 DEG C of following stirring and emulsifying emulsifying 10min that continue, and adds 19.5mL25% glutaraldehyde chemical cross-linking agent with thread, stirs crosslinking curing 1h, with isopropanol dehydration, washing, sucking filtration; Wash again the liquid paraffin of microsphere surface off with a small amount of petroleum ether, vacuum drying 24h, the sterilizing of Co 60 x ray irradiation x, obtains faint yellow valnemulin hydrochloride lung-targeted microspheres.
By observation by light microscope microsphere shape, measure particle diameter, its content of high effective liquid chromatography for measuring with laser particle size analyzer.Result valnemulin hydrochloride gelatine microsphere mode of appearance rounding, good dispersion, mean diameter is 12.85 μ m, particle size distribution accounts for 92.5% of sum at the microsphere of 7～30 μ m.Microsphere drug loading is 20.45 ± 2.61%, and envelop rate is 90.37 ± 1.62%.
embodiment 4 acid hydrochloride salt valnemulin microsphere preparation examples 4
Taking gelatin 1.5g puts in beaker, add 20mL ultra-pure water, complete swelling in 60 DEG C of water-baths, add again 2g micronization valnemulin hydrochloride (100-300 order) and 4g PVP, mix dissolving, then splashing in the container that fills 3.0mL department class 80 and 200mL liquid paraffin, is 900rmin at 65 DEG C, mixing speed
-1electromagnetic agitation 20min, makes colostrum, puts into rapidly ice-water bath temperature and is down to 4 DEG C of following stirring and emulsifying emulsifying 10min that continue, and adds 11mL25% glutaraldehyde chemical cross-linking agent with thread, stirs crosslinking curing 1h, with isopropanol dehydration, washing, sucking filtration; Wash again the liquid paraffin of microsphere surface off with a small amount of petroleum ether, vacuum drying 24h, the sterilizing of Co 60 x ray irradiation x, obtains faint yellow valnemulin hydrochloride lung-targeted microspheres.
By observation by light microscope microsphere shape, measure particle diameter, its content of high effective liquid chromatography for measuring with laser particle size analyzer.Result valnemulin hydrochloride gelatine microsphere mode of appearance rounding, good dispersion, mean diameter is 10.96 μ m, particle size distribution accounts for 88.4% of sum at the microsphere of 7～30 μ m.Microsphere drug loading is 18.45 ± 1.90%, and envelop rate is 86.24 ± 1.53%.
embodiment 5 acid hydrochloride salt valnemulin microsphere preparation examples 5
Taking gelatin 2g puts in beaker, add 20mL ultra-pure water, complete swelling in 60 DEG C of water-baths, add again 2g micronization valnemulin hydrochloride (100-300 order) and 6g PVP, mix dissolving, then splashing in the container that fills 2.1mL department class 80 and 140mL liquid paraffin, is 900rmin at 70 DEG C, mixing speed
-1electromagnetic agitation 20min, makes colostrum, puts into rapidly ice-water bath temperature and is down to 4 DEG C of following stirring and emulsifying emulsifying 10min that continue, and adds 8.4mL25% glutaraldehyde chemical cross-linking agent with thread, stirs crosslinking curing 1h, with isopropanol dehydration, washing, sucking filtration; Wash again the liquid paraffin of microsphere surface off with a small amount of petroleum ether, vacuum drying 24h, the sterilizing of Co 60 x ray irradiation x, obtains faint yellow valnemulin hydrochloride lung-targeted microspheres.
By observation by light microscope microsphere shape, measure particle diameter, its content of high effective liquid chromatography for measuring with laser particle size analyzer.Result valnemulin hydrochloride microsphere mode of appearance rounding, good dispersion, mean diameter is 12.06 μ m, particle size distribution accounts for 90.2% of sum at the microsphere of 7～30 μ m.Microsphere drug loading is 21.55 ± 2.30%, and envelop rate is 87.39 ± 1.66%.
the study on the stability of embodiment 6 valnemulin hydrochloride lung-targeted microspheres
1, accelerated test
Getting 3 batches of valnemulin hydrochloride lung-targeted microspheres prepared by embodiment 2 is sealed in cillin bottle, under the condition of 25 DEG C (RH75%), in testing chamber for medicine stability, place 6 months, sample respectively once the 1st, 2,3,6 the end of month, investigate microsphere cosmetic variation, and carry out the mensuration of drug loading and envelop rate.
2, strong illumination test
Getting 3 batches of valnemulin hydrochloride microspheres prepared by embodiment 2 is sealed in cillin bottle, sealing, under the condition that is 4500 ± 500lx in intensity of illumination, in testing chamber for medicine stability, place 10 days, in the 5th, 10 days timing samplings, investigate the cosmetic variation of valnemulin hydrochloride microsphere, and in the form of optical microphotograph Microscopic observation microsphere, and carry out drug loading and entrapment efficiency determination, examine the stability of microsphere under strong illumination condition.
Valnemulin hydrochloride microsphere accelerated test result and strong illumination result of the test are respectively in table 1 and table 2.From table, in result, can find out that outward appearance, form, content drug loading and the envelop rate of valnemulin hydrochloride microsphere all change not quite, show higher stability.
the targeting test of embodiment 7 valnemulin hydrochloride microspheres in rabbit body
materials and methods
test drug
The valnemulin hydrochloride microsphere of preparing according to embodiment 2.
experimental animal
48 healthy new zealand rabbits, body weight 2.5～2.8kg, male and female half and half.
test method
Select 48 new zealand rabbits, body weight 2.5～2.8kg, male and female half and half.Feed the complete feed not contain antibacterials.Raise in advance 1 week.Fasting 12h before administration, freely drinks water, and 4h after administration allows its free choice feeding.After 1 week, before administration, weigh and number, be divided at random 2 groups of valnemulin hydrochloride microsphere and valnemulin hydrochloride injection, every group by only pressing 5mg/kg intravenous injection, 15min, 30min, 45min, 1h, 2h, 4h, 8h, 12h, 24h, 36h, 48h, 72h after administration takes a blood sample and puts to death rabbit respectively, cut open rapidly and get each internal organs 10g, sealing ,-20 DEG C of preservations are to be measured.When mensuration, adopt high effective liquid chromatography for measuring blood, organize Chinese medicine concentration, pharmacokinetic parameter carries out curve fitting according to the 3p97 pharmacokinetics program software of Chinese Pharmacological Society's establishment, calculates area under the drug-time curve (AUC) and peak concentration (Cp).Adopt following targeting parameter evaluation medicine lung targeted characteristic.
Re= AUCm/AUCi
The non-target organ of Te=AUC target organ/AUC
Ce=Cpm/Cpi
Re is relative uptake ratio, and Re > 1 shows that microsphere makes the dose of target organ lung acceptance higher than injection; Te is targeting efficiency, and Te > 1 represents that microsphere is more selective than non-target organ to target organ lung, and Te value is larger, and selectivity is stronger.Ce is peak concentration ratio, and the effect that microsphere changes drug distribution is described, Ce > 1 represents to distribute to be increased, and Ce < 1 represents to distribute and reduces.Wherein m represents microsphere, and i represents injection.
result of the test
Result of the test is in table 3.
Result demonstration, the targeting efficiency of valnemulin hydrochloride lung-targeted microspheres lung has improved respectively 5.77,4.57,2.67 times compared with muscle, liver and kidney; The Re maximum (being 3.13) of lungs, shows that the ability of valnemulin in lung picked-up microsphere is the strongest; Lung, liver, kidney, muscle Ce value are respectively 2.36,1.24,0.91,0.95, and showing has significantly increased its distribution at lung after valnemulin hydrochloride is made microsphere, have reduced the distribution at kidney, liver and muscle.
Claims (7)
1. a valnemulin hydrochloride microsphere, is characterized in that, is made up of water, oil phase and cross-linking agent, and wherein the volume ratio of water and oil phase is 1:6-12;
Described water is composed of the following components: gelatin, valnemulin hydrochloride, polyvinylpyrrolidone and purified water, wherein the bulking value specific concentration of gelatin is 7.5-15%, the bulking value specific concentration of valnemulin hydrochloride is 5-20%, and the weight ratio of polyvinylpyrrolidone and valnemulin hydrochloride is 0.5-3:1;
Described oil phase is made up of emulsifying agent and liquid paraffin, and wherein the volume of emulsifying agent is the 1-2.5% of oil phase volume;
Described cross-linking agent is glutaraldehyde, and its volume is the 3-7.5% of water and oil phase cumulative volume.
2. a kind of valnemulin hydrochloride microsphere as claimed in claim 1, it is characterized in that, described polyvinylpyrrolidone be selected from one in PVP k10, polyvinylpyrrolidone k25, polyvinylpyrrolidone k30 or polyvinylpyrrolidone k50, two or more.
3. a kind of valnemulin hydrochloride microsphere as claimed in claim 1, is characterized in that, described emulsifying agent is class of department 80.
4. a preparation method for a kind of valnemulin hydrochloride microsphere as claimed in claim 1, is characterized in that, preparation process is:
(a) by valnemulin hydrochloride micronization, and cross 100-300 mesh sieve, the gelatin that takes recipe quantity is put in beaker, add appropriate purified water fully swelling, after water bath with thermostatic control, then add micronization valnemulin hydrochloride and the polyvinylpyrrolidone of recipe quantity, stir and obtain water;
(b) measure class of department 80 and the liquid paraffin of recipe quantity, put in beaker and stir on electric heating magnetic stirring apparatus, obtain oil phase;
(c) water is added drop-wise in oil phase, electric heating magnetic agitation 15-20min, makes colostrum, put into rapidly ice-water bath, temperature is down to 4 DEG C of following continuation emulsifyings and is obtained emulsification system, adds 25% glutaraldehyde chemical cross-linking agent with thread, stir crosslinking curing, with isopropanol dehydration, washing, sucking filtration;
(d) wash the liquid paraffin of microsphere surface off with petroleum ether, vacuum drying 24h, the sterilizing of Co 60 x ray irradiation x, obtains valnemulin hydrochloride lung-targeted microspheres.
5. the preparation method of a kind of valnemulin hydrochloride microsphere as claimed in claim 4, is characterized in that, in described step (a), the temperature of water bath with thermostatic control is 50-70 DEG C.
6. the preparation method of a kind of valnemulin hydrochloride microsphere as claimed in claim 4, is characterized in that, in described step (b), the temperature of electric heating magnetic stirrer is 50-70 DEG C.
7. the preparation method of a kind of valnemulin hydrochloride microsphere as claimed in claim 4, it is characterized in that, the mixing speed of the stirring crosslinking curing in described step (b) and step (c) in mixing speed and the step (c) of electric heating magnetic agitation is 600-1200rmin
-1.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108853022A (en) * | 2017-05-16 | 2018-11-23 | 北京科百大科技有限责任公司 | A kind of preparation method of stable valnemulin hydrochloride composition |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102579364A (en) * | 2012-03-05 | 2012-07-18 | 河北科技大学 | Sustained or controlled release microsphere of valnemulin/valnemulin salts and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102579364A (en) * | 2012-03-05 | 2012-07-18 | 河北科技大学 | Sustained or controlled release microsphere of valnemulin/valnemulin salts and preparation method thereof |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108853022A (en) * | 2017-05-16 | 2018-11-23 | 北京科百大科技有限责任公司 | A kind of preparation method of stable valnemulin hydrochloride composition |
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