CN103417484A - Wettable doramectin solid dispersion powder and preparation method and application thereof - Google Patents
Wettable doramectin solid dispersion powder and preparation method and application thereof Download PDFInfo
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- CN103417484A CN103417484A CN2013103669588A CN201310366958A CN103417484A CN 103417484 A CN103417484 A CN 103417484A CN 2013103669588 A CN2013103669588 A CN 2013103669588A CN 201310366958 A CN201310366958 A CN 201310366958A CN 103417484 A CN103417484 A CN 103417484A
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Abstract
The invention provides wettable doramectin solid dispersion powder. Raw materials and auxiliary materials for preparing pharmaceutical preparations of the wettable doramectin solid dispersion powder include 0.2 to 10 parts of doramectin, 2 to 20 parts of hydroxypropyl-beta-cyclodextrin, 8 to 2.5 parts of tween-800, 57.5 to 79 parts of anhydrous glucose, ,10 to 18 parts of anhydrous sodium citrate, and antioxidant which is 0.02 to 0.05% w/w of the doramectin and which is selected from one or a combination of two of hydroxy butyl toluene, butyl hydroxy anisole and propyl gallate. The invention further provides a preparation method and application. The wettable doramectin solid dispersion powder can be obtained by screening the auxiliary materials, dispersion of the doramectin can be guaranteed effectively, treatment effect of the doramectin preparations is improved significantly, and a new selection is provided for clinical pharmaceutical use.
Description
Technical field
The present invention relates to a kind of wettability doractin solid minute loose powder and its production and use.
Background technology
Doractin (Doramectin) is the Macrolide antiparasitic of new generation of developing the nineties in 20th century, that to take thiacyclohexane carboxylic acid (Cyclohexanecarboxylic acid) be precursor, a kind of Avermectins antibiotic that Avid kyowamycin (Streptomycete avermitilis) strain fermentation by gene recombinaton forms, the main difference of molecular structure and ivermectin is that the C25 position is that cyclohexyl replaces.Its anthelmintic mechanism is identical with ivermectin, is all the realization that is used for by reinforcing gamma-amino butyric acid (GABA).
Research shows, doractin is for cattle, and the expeling rate of cross-ox-eye worm (Thelazia skryabini, Da Kou suck trematodiasis) is 100%; To the adults of 15 kinds of nematicides such as Ostertagia orloffi, lyrate oersted nematicide, Bai Shi haemonchus and the 4th the phase larva, and Dictyocaulus viviparus and cattle surpass 99% with the expeling rate of worm (sucking nematicide) adult; To Trichostrongylus longispicularis expeling rate, be 93%～99%; To blunt thorn nematodirus expeling rate, be 96.5%; To Trichocephalus expeling rate, be 92.3%～94.6%.Doractin is the same with ivermectin and moxidectin, all that a subcutaneous injection can maintain the drug effect medicine of several weeks, the cattle of artificial challenge's cooperia oncophora larva for example, with after doractin when 14 days and 21 days worm reduction rate be respectively 99.2% and 90.7%, equally, the attack against each other worm reduction rate of Ostertagia orloffi of worm 21 days and 28 days is respectively 99.9% and 93.7%; Viviparous Ah's filaria is respectively to 100% and 99.9%.Naturally herd test, confirm according to the faecal egg counting, the application doractin can reach 19～22 days to the useful effect of Ostertagia orloffi and cooperia oncophora.Doractin is also very effective to cattle inside and outside various segmental appendage class parazoon.100% effective natural infection polypide has itch mite, acaricide, blood louse, bomb fly (1,2,3 ecdysis).Doractin is the same with other avilamycin to the ox louse effective percentage is 82%, but more effective to the cone fly, can be after medication in 14 days, 100% prevents that calf from infecting.
Doractin to ascaris suum, Strongyloides ransomi, red Metastrongylus apri adult and the 4th the phase larva, and Pulmonis Sus domestica nematicide (rear strongylid), Ren sus domestica worm (stephanurus dentatus) adult all have splendid dispel effect.Doractin also has good repelling and killing efficacy to Sarcoptes suis, haematopinus suis adult and immaturity polypide.
Doractin is considered to one of classic anti-parasite medicine in current avilamycin family, for the inside and outside double agent of killing, nematicide, arthropod is all had to good repelling and killing efficacy.With other commercially available avilamycin series products, compare, wider general, the better effects if of its parasiticide, and also the effective time that the prevention parasite infects again is longer, is one of antiparasite drugs for animals had at present potentiality to be exploited.But, due to the poorly water-soluble of itself, existing doractin preparation seldom, and usually adds irritant stronger organic solvent, so certain zest is arranged during clinical practice, its application is very restricted.Therefore, in order to allow doractin better applied aspect livestock-raising and raising pets, develop and a kind ofly be applicable to varying number fauna, steady quality, the doractin novel formulation that easy to use and side effect is less is very important.
Summary of the invention
Technical scheme of the present invention has been to provide a kind of wettability doractin solid minute loose powder.Another technical scheme of the present invention has been to provide the preparation method of this wettability doractin solid minute loose powder.
The invention provides a kind of wettability doractin solid minute loose powder, it is the pharmaceutical preparation that the supplementary material by the following weight proportioning is prepared from:
0.2～10 part of doractin, 2～20 parts of HP-β-CD, 0.8～2.5 part of tween 80,57.5～79 parts of anhydrous glucose, 10～18 parts, anhydrous citric acid sodium, antioxidant; 0.02～0.05%w/w that described antioxidant consumption is doractin;
Antioxidant is selected from the one or more kinds of combinations in hydroxy toluene butyl ester, Butylated hydroxyanisole, propyl gallate.
Further, it is the pharmaceutical preparation that the supplementary material by the following weight proportioning is prepared from:
0.6～4 part of doractin, 4.8～16 parts of HP-β-CD, 1.2～2 parts of tween 80s, 66～77.4 parts of anhydrous glucose, 12～16 parts, anhydrous citric acid sodium, antioxidant; The 0.02%w/w that described antioxidant consumption is doractin.
Further, it is the pharmaceutical preparation that the supplementary material by the following weight proportioning is prepared from:
1.6～4 parts of doractins, 9.6～16 parts of HP-β-CD, 1.6～2 parts of tween 80s, 66～73.2 parts of anhydrous glucose, 12～14 parts, anhydrous citric acid sodium; The 0.02%w/w that oxidation preventive content is doractin.
Preferably, it is the pharmaceutical preparation that the supplementary material by the following weight proportioning is prepared from:
1.6 parts of doractins, 9.6 parts of HP-β-CD, 1.6 parts of tween 80s, 73.2 parts of anhydrous glucose, 14 parts, anhydrous citric acid sodium, the 0.02%w/w that hydroxy toluene butyl ester content is doractin;
Perhaps, 4 parts of doractins, 16 parts of HP-β-CD, 2 parts of tween 80s, 66 parts of anhydrous glucose, 12 parts, anhydrous citric acid sodium, the 0.02%w/w that hydroxy toluene butyl ester content is doractin.
The present invention also provides the preparation method of above-mentioned wettability doractin solid minute loose powder, and it is characterized in that: it comprises the steps:
A. take by weight ratio supplementary material;
B. get doractin, HP-β-CD, tween 80, add dehydrated alcohol and antioxidant, stirring and dissolving, then add anhydrous glucose and anhydrous citric acid sodium mix homogeneously, and dry, pulverize, obtain wettability doractin solid minute loose powder.
The present invention also provides the purposes of above-mentioned wettability doractin solid minute loose powder in the veterinary drug of preparation anthelmintic.
The present invention screens the wettability doractin solid minute loose powder obtained by adjuvant, not only can effectively guarantee the dispersibility of doractin, has also significantly improved the therapeutic effect of doractin preparation, for clinical application provides new selection.
The specific embodiment
Embodiment 1 wettability doractin of the present invention solid divides the preparation of loose powder
Get doractin 0.02kg, HP-β-CD 0.2kg, tween 80 0.08kg, add dehydrated alcohol 200ml, Butylated hydroxyanisole 4mg, be stirred to dissolve, add anhydrous glucose 7.9kg, anhydrous citric acid sodium 1.8kg, mix homogeneously, 50 ℃ of oven dry of ventilating, pulverize, and obtains the present invention's 0.2% wettability doractin solid minute loose powder.
Embodiment 2 wettability doractin of the present invention solid divides the preparation of loose powder
Get doractin 0.2kg, HP-β-CD 1.2kg, tween 80 0.2kg, add dehydrated alcohol 1000ml, hydroxy toluene butyl ester 40mg, be stirred to dissolve, add anhydrous glucose 15.6kg, anhydrous citric acid sodium 2.8kg, mix homogeneously, 50 ℃ of oven dry of ventilating, pulverize, and obtains the present invention's 1.0% wettability doractin solid minute loose powder.
Embodiment 3 wettability doractin of the present invention solid divides the preparation of loose powder
Get doractin 1.0kg, HP-β-CD 4.0kg, tween 80 0.5kg, add dehydrated alcohol 2000ml, propyl gallate 200mg, be stirred to dissolve, add anhydrous glucose 16.5kg, anhydrous citric acid sodium 3kg, mix homogeneously, 50 ℃ of oven dry of ventilating, pulverize, and obtains the present invention's 5.0% wettability doractin solid minute loose powder.
Embodiment 4 wettability doractin of the present invention solid divides the formula screening of loose powder
Being used in combination etc. of supplementary product kind, consumption and adjuvant, be the key factor of preparation, and their can bring material impact to the quality of the pharmaceutical preparations and preparation (producing/preparation) process.For wettability solid minute loose powder for animals, its dispersion of major effect and sedimentation velocity etc.The solid of be uniformly dispersed in order to prepare, sedimentation velocity is slower minute loose powder, the present invention screens preparation prescription.
(1) preparation of different formulations product
By lower the regulation containing measuring doractin, HP-β-CD, tween 80 of each formula in table 1, add appropriate dehydrated alcohol, add again antioxidant hydroxy toluene butyl ester (doractin content 0.02%), be stirred to dissolve, add anhydrous glucose and anhydrous citric acid sodium by a corresponding formula lower ormal weight, be mixed into the moistening soft material, 50 ℃ of oven dry of ventilating, pulverize, prepare wettability doractin solid of the present invention and divide loose powder.
Table 1 wettability doractin of the present invention solid divides the preferred version of loose powder formula
(2) quality evaluation of different formulations product
Dispersion is estimated: get each 1g of wettability doractin solid minute loose powder by 1～6 preparations of filling a prescription of table 1 formula, drop in 1000ml water, observe or stir and observe its deployment conditions.Disperse slower and inhomogeneous being chosen as " poor "; Disperse slower, in dispersive process, have the caking or granule, agitation as appropriate can be uniformly dispersed, and is chosen as " qualified "; Disperse soon, gentle agitation can be uniformly dispersed, and is chosen as " good "; Disperse soon, need not stir and can be uniformly dispersed, be chosen as " excellent ".The results are shown in Table 2.
Settling volume is than measuring: by " solution for oral administration in " People's Republic of China's veterinary drug allusion quotation (version in 2010) " appendix, suspensoid for oral administration, Emulsion for oral administration " settling volume is than inspection technique requirement, wettability doractin solid minute loose powder by formula 1～6 preparations of filling a prescription is carried out to settling volume than measuring, sample thief 0.25g puts in 50ml tool plug graduated cylinder, add water to 50ml, fill in close, jolting 1min exerts oneself, write down suspended matter and start height H 0, within standing 3 hours, write down the final height H of suspended matter, be calculated as follows: settling volume ratio=H/H0, the settling volume ratio should be not less than 0.90.The results are shown in Table 2.
Table 2 wettability doractin of the present invention solid disperses opaque amount evaluation result
Listed 4 indexs of his-and-hers watches 1 are carried out analysis-by-synthesis and can be obtained: fill a prescription 2～it is 6 all qualified to fill a prescription, wherein take again and fill a prescription 4, fill a prescription 5 as optimum.
Below illustrate beneficial effect of the present invention by test example.
The oral wettability doractin of test example 1 solid divides the clinical tests of loose powder to the pig acariasis
Material: ivermectin powder (0.2%, commercially available prod); Wettability doractin solid divides loose powder (0.2%, embodiment, 1 preparation).
Case: pig acarid case 48 examples of Chengdu suburbs and counties under the jurisdiction of a large city first pig farm natural occurrence (sick pig becomes thin, down in spirits, and happiness, in wall friction, is frayed the vesicle that occurs after skin, incrustation, depilation etc. as seen; Collect the scurf of disease pig injury moistening, directly be coated on microscope slide, can be observed demodicid mite alive).
Method: select the clinical onset growing and fattening pigs that body weight is substantially suitable, in same pig house, under identical raising condition, be divided at random matched group, test group and negative control group; Matched group by 0.1% concentration spice, supplies sick pig feeding with commercially available ivermectin powder, is used in conjunction 3; Test group is converted drinking water by the wettability doractin solid minute loose powder of embodiment 1 preparation by 0.05% concentration, for sick pig, drinks, and is used in conjunction 3 days; Negative control group is raised by daily feeding manner, not administration.
The efficacy determination method: medication is after 5 days, and it is normal that spiritual appetite is recovered, and microscopy, without parasite or the worm's ovum of living, is judged to recovery from illness; After medication 5 days, spiritual appetite takes a turn for the better, and the visible a small amount of parasite lived of microscopy, be judged to effectively; After medication 5 days, symptom is not improved, and it is invalid to be judged to.
Experimental result: in Table 3.
The oral wettability doractin of table 3 solid divides the clinical tests result of loose powder to the pig acariasis
As can be seen from the test results, oral wettability doractin solid minute loose powder of the present invention all is better than commercially available ivermectin powder to the therapeutic effect of pig acariasis.The convenience that wettability doractin solid of the present invention minute loose powder is used is better than commercially available ivermectin powder, greatly reduces the working strength of administration.Also find in test, due to the mode administration of taking drinking-water to add, wettability doractin solid minute loose powder of the present invention does not in use affect the feed intake of disease pig.
Test example 2 injection wettability doractin solids divide the clinical tests of loose powder to the pig acariasis
Material: Doramectin injection fluid (0.2%, commercially available prod); Wettability doractin solid divides loose powder (5.0%, embodiment, 3 preparations).
Case: pig acarid case 56 examples of Chengdu suburbs and counties under the jurisdiction of a large city second pig farm natural occurrence (sick pig becomes thin, down in spirits, and happiness, in wall friction, is frayed the vesicle that occurs after skin, incrustation, depilation etc. as seen; Collect the scurf of disease pig injury moistening, directly be coated on microscope slide, can be observed demodicid mite alive).
Method: select the clinical onset growing and fattening pigs that body weight is substantially suitable, in same pig house, under identical raising condition, be divided at random matched group, test group and negative control group; The commercially available Doramectin injection fluid of matched group subcutaneous injection; Test group is watered intramuscular injection by the wettability doractin solid minute loose powder of embodiment 3 preparations by 4% concentration; Negative control group is raised by daily feeding manner, not administration.
Efficacy determination method: with test 1.
Experimental result: in Table 4.
Table 4 injection wettability doractin solid divides the clinical tests result of loose powder to the pig acariasis
Can find out from above result of the test, inject wettability doractin solid minute loose powder of the present invention the therapeutic effect of pig acariasis all is better than to commercially available Doramectin injection fluid.The convenience that wettability doractin solid of the present invention minute loose powder is used is better than commercially available Doramectin injection fluid, greatly reduces the working strength of administration.Also find in test, inject wettability doractin solid of the present invention and divide loose powder less to the stimulation of sick pig.
In sum, the present invention screens the wettability doractin solid minute loose powder obtained by adjuvant, not only can effectively guarantee the dispersibility of doractin, has also significantly improved the therapeutic effect of doractin preparation, for clinical application provides new selection.
Claims (6)
1. a wettability doractin solid divides loose powder, it is characterized in that: it is the pharmaceutical preparation that the supplementary material by the following weight proportioning is prepared from:
0.2～10 part of doractin, 2～20 parts of HP-β-CD, 0.8～2.5 part of tween 80,57.5～79 parts of anhydrous glucose, 10～18 parts, anhydrous citric acid sodium, antioxidant; 0.02～0.05%w/w that described antioxidant consumption is doractin;
Antioxidant is selected from the one or more kinds of combinations in hydroxy toluene butyl ester, Butylated hydroxyanisole, propyl gallate.
2. wettability doractin solid according to claim 1 divides loose powder, it is characterized in that: it is the pharmaceutical preparation that the supplementary material by the following weight proportioning is prepared from:
0.6～4 part of doractin, 4.8～16 parts of HP-β-CD, 1.2～2 parts of tween 80s, 66～77.4 parts of anhydrous glucose, 12～16 parts, anhydrous citric acid sodium, antioxidant; The 0.02%w/w that described antioxidant consumption is doractin.
3. wettability doractin solid according to claim 2 divides loose powder, it is characterized in that: it is the pharmaceutical preparation that the supplementary material by the following weight proportioning is prepared from:
1.6～4 parts of doractins, 9.6～16 parts of HP-β-CD, 1.6～2 parts of tween 80s, 66～73.2 parts of anhydrous glucose, 12～14 parts, anhydrous citric acid sodium; The 0.02%w/w that oxidation preventive content is doractin.
4. wettability doractin solid according to claim 3 divides loose powder, it is characterized in that: it is the pharmaceutical preparation that the supplementary material by the following weight proportioning is prepared from:
1.6 parts of doractins, 9.6 parts of HP-β-CD, 1.6 parts of tween 80s, 73.2 parts of anhydrous glucose, 14 parts, anhydrous citric acid sodium, the 0.02%w/w that hydroxy toluene butyl ester content is doractin;
Perhaps, 4 parts of doractins, 16 parts of HP-β-CD, 2 parts of tween 80s, 66 parts of anhydrous glucose, 12 parts, anhydrous citric acid sodium, the 0.02%w/w that hydroxy toluene butyl ester content is doractin.
5. the described wettability doractin of claim 1～4 an any one solid divides the preparation method of loose powder, and it is characterized in that: it comprises the steps:
A. take by weight ratio supplementary material;
B. get doractin, HP-β-CD, tween 80, add dehydrated alcohol and antioxidant, stirring and dissolving, then add anhydrous glucose and anhydrous citric acid sodium mix homogeneously, and dry, pulverize, obtain wettability doractin solid minute loose powder.
6. the described wettability doractin of claim 1～4 any one solid divides the purposes of loose powder in the veterinary drug of preparation anthelmintic.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101292981A (en) * | 2007-04-29 | 2008-10-29 | 杨喜鸿 | Solid dispersion, composition of rimonabant, preparation and medicament application thereof |
| CN103083243A (en) * | 2011-11-03 | 2013-05-08 | 青岛康地恩药业股份有限公司 | Doramectin soluble powder and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101292981A (en) * | 2007-04-29 | 2008-10-29 | 杨喜鸿 | Solid dispersion, composition of rimonabant, preparation and medicament application thereof |
| CN103083243A (en) * | 2011-11-03 | 2013-05-08 | 青岛康地恩药业股份有限公司 | Doramectin soluble powder and preparation method thereof |
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Address after: 611130 Wenjiang, Chengdu, Chengdu cross strait science and Technology Industrial Development Zone, Jin Fu Road, Sichuan Patentee after: Chengdu Qiankun animal pharmaceutical Limited by Share Ltd Patentee after: Shanghai Simenon Biotech Co., Ltd. Address before: 611130 Wenjiang, Chengdu, Chengdu cross strait science and Technology Industrial Development Zone, Jin Fu Road, Sichuan Patentee before: Chengdu Qiankun Animal Pharmaceutical Co.,Ltd. Patentee before: Shanghai Simenon Biotech Co., Ltd. |