CN101862293B - Doxycycline hydrochloride oil turbid liquor, preparation method and application thereof - Google Patents
Doxycycline hydrochloride oil turbid liquor, preparation method and application thereof Download PDFInfo
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- CN101862293B CN101862293B CN2010102075358A CN201010207535A CN101862293B CN 101862293 B CN101862293 B CN 101862293B CN 2010102075358 A CN2010102075358 A CN 2010102075358A CN 201010207535 A CN201010207535 A CN 201010207535A CN 101862293 B CN101862293 B CN 101862293B
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Abstract
The invention discloses doxycycline hydrochloride oil turbid liquor, a preparation method and application thereof. The doxycycline hydrochloride oil turbid liquor of the invention is obtained through preparing 50 to 300g of doxycycline hydrochloride raw medicine, 1 to 50g of suspending aids, 1 to 30g of surface active agents, 0.1 to 2g of oxidation inhibitors and a proper amount of oil into the oil turbid liquor with the volume amount of 1L. The doxycycline hydrochloride oil turbid liquor of the invention is prepared by a dispersing method, has the advantages of high stability, prolonged absorption time, delayed peak reaching time, prolonged elimination half life and good biocompatibility, and can be used as long-effect injection preparations for animals.
Description
Technical field
The invention belongs to antibiotic medicine technical field for animals, be specifically related to a kind of oil suspension of doxycycline hydrochloride.
Background technology
Doxycycline hydrochloride has another name called abadox, doxycycline hyclate, belongs to tetracycline medication, is used for treatment on the veterinary clinic by gram positive bacteria, negative bacterium and some chlamydia, mycoplasma, rickettsia, the caused disease of spirillum.
Doxycycline mainly contains injectable powder, tablet, aqueous injection etc. in veterinary drug dosage form commonly used clinically at present.But tablet and injectable powder administration are inhomogeneous, and are vulnerable to the gastrointestinal content influence and the reduction therapeutic effect.Common doxycycline aqueous injection content of dispersion is low, often needs repetitively administered, and need administration 1 general every day; Cause the animal stress easily; And plasma concentration curve generally is wavy, and tangible crest and trough can appear in blood drug level, and this also can produce certain toxic and side effects to animal.For fear of above-mentioned drawback, reduce administration number of times, prolong holding time of effective blood drug concentration, improve its stability and biocompatibility, research and development doxycycline long-acting oil suspension injection has great significance clinical.
Summary of the invention
The objective of the invention is to overcome the deficiency of existing doxycycline hydrochloride dosage form; A kind of novel form of doxycycline hydrochloride is provided; A kind of oil suspension of doxycycline hydrochloride; Can improve doxycycline hydrochloride stability of drug and biocompatibility, make its tool long-acting, strengthen the doxycycline hydrochloride curative effect.
Another object of the present invention provides the method for preparing of the oil suspension of said doxycycline hydrochloride.
A further object of the invention provides the application of the oil suspension of said doxycycline hydrochloride.
The object of the invention is achieved through following technical scheme:
A kind of oil suspension of doxycycline hydrochloride is provided, it is characterized in that every liter of doxycycline hydrochloride oil suspension comprises each component of following weight:
Doxycycline hydrochloride crude drug: 50～300g;
Suspending agent: 1～50g;
Surfactant: 1～30g;
Antioxidant: 0.1～2g;
Oil phase: add to 1 liter.
Said oil phase preferably vegetable oil, the mixture of one or more any ratios in optional soybean oil, Oleum Gossypii semen, Oleum Arachidis hypogaeae semen, Oleum Sesami, Semen Maydis oil, Oleum Camelliae, Oleum Helianthi, Oleum Ricini or the olive oil.
Described suspending agent comprises carboxymethyl cellulose (sodium), methylcellulose, arabic gum, xanthan gum, polyvinylpyrrolidone, the molecular weight mixture greater than one or more any ratios of 1000 Polyethylene Glycol, castor oil hydrogenated or aluminum monostearate.
Said surfactant comprises the mixture of one or more any ratios of lecithin, soybean phospholipid, fatty glyceride, sucrose fatty acid ester, polyoxyethylene sorbitan fatty acid ester (Tween series), sorbitan fatty acid ester (Span series), polyoxyethylene fatty acid ester (Myrij series) or polyoxyethylene aliphatic alcohol ether (Brij series).
Said antioxidant is lipophile antioxidant, comprises the mixture of one or more any ratios in gallic acid and esters thereof, butylated hydroxyarisol (BHA), dibenzylatiooluene (BHT), tocopherol or the ascorbyl palmitate.
The method for preparing of said doxycycline hydrochloride oil suspension is proportionally weighing doxycycline hydrochloride crude drug and suspending agent, surfactant, antioxidant and oil phase; Under aseptic condition; Through the colloid mill mix homogeneously, promptly get the oil suspension of doxycycline hydrochloride.
The present invention provides the application of oil suspension aspect preparation long-acting veterinary injection of said doxycycline hydrochloride, the application that especially is applied to prepare treatment swine eperythrozoonosis or mycoplasma medicine aspect simultaneously.
The invention has the beneficial effects as follows:
First Application vegetable oil of the present invention is the oil suspension that disperse medium prepares doxycycline hydrochloride; Search out suitable component compatibility and accurate ratio, adopt simple method for preparing successfully to prepare the oil suspension of doxycycline hydrochloride, effectively improved stability of drug; Solved the zest problem that conventional injection with an organic solvent causes; The animal compliance is good, and preparation forms drug depot in vivo, the effect of performance slow release long-acting.The oil suspension of doxycycline hydrochloride of the present invention can be applicable to the long-acting veterinary injection, stability, good biocompatibility, and tool delayed absorption effect provides a kind of new preparation for China's veterinary clinic utilizes doxycycline hydrochloride better.
The specific embodiment
Specify the present invention below in conjunction with specific embodiment, the simple substitute of said suspending agent, surfactant, antioxidant, oil phase is not given unnecessary details in an embodiment one by one, but does not therefore limit practical range of the present invention.
Embodiment 1:20% doxycycline hydrochloride oil suspension
Prepare each component according to following ratio, all components is medicinal conventional raw material (commercial):
Doxycycline hydrochloride crude drug: 200g;
Aluminum monostearate: 5g;
Sorbester p17: 2g;
Propyl gallate: 0.5g;
Oleum Camelliae: add to 1000mL.
Method for preparing is according to aforementioned proportion weighing doxycycline hydrochloride crude drug, aluminum monostearate, sorbester p17, propyl gallate and Oleum Camelliae, under aseptic condition, through the colloid mill mix homogeneously, promptly gets the oil suspension of doxycycline hydrochloride.Colloid mill is not done specific (special) requirements, reaches the mix homogeneously requirement and gets final product.
Embodiment 2:10% doxycycline hydrochloride oil suspension
Prepare each component according to following ratio, all components is medicinal conventional materials:
Doxycycline hydrochloride crude drug: 100g;
Aluminum monostearate: 5g;
Castor oil hydrogenated: 5g;
Soybean phospholipid: 1g;
Sorbester p17: 2g;
BHA： 0.1g；
BHT： 0.1g；
Oleum Arachidis hypogaeae semen: 300g;
Oleum Camelliae adds to 1000mL.
Method for preparing is according to aforementioned proportion weighing doxycycline hydrochloride crude drug, aluminum monostearate, castor oil hydrogenated, soybean phospholipid, sorbester p17, BHA, BHT, Oleum Arachidis hypogaeae semen and Oleum Camelliae; Under aseptic condition; Through the colloid mill mix homogeneously, promptly get the oil suspension of doxycycline hydrochloride.
Embodiment 3:5% doxycycline hydrochloride oil suspension
Prepare each component according to following ratio, all components is medicinal conventional raw material:
Doxycycline hydrochloride crude drug: 50g;
Polyvinylpyrrolidone: 10g;
Soybean phospholipid: 2g;
Ascorbyl palmitate: 0.2g;
Semen Maydis oil: add to 1000mL.
Method for preparing is according to aforementioned proportion weighing doxycycline hydrochloride crude drug, polyvinylpyrrolidone, soybean phospholipid, ascorbyl palmitate and Semen Maydis oil, under aseptic condition, through the colloid mill mix homogeneously, promptly gets the oil suspension of doxycycline hydrochloride.
Embodiment 4:30% doxycycline hydrochloride oil suspension
Prepare each component according to following ratio, all components is medicinal conventional raw material:
Doxycycline hydrochloride crude drug: 300g;
Castor oil hydrogenated: 10g;
Fatty glyceride: 10g;
BHT： 0.5g；
Soybean oil: add to 1000mL.
Method for preparing is according to aforementioned proportion weighing doxycycline hydrochloride crude drug, castor oil hydrogenated, fatty glyceride, BHT and soybean oil, under aseptic condition, through the colloid mill mix homogeneously, promptly gets the oil suspension of doxycycline hydrochloride.
Embodiment 5: doxycycline hydrochloride oil suspension character test of the present invention
1, quality evaluation
Doxycycline hydrochloride oil suspension of the present invention is not seen layering after placing 30min, the settling volume ratio is 95% behind the placement 3h, explains that the suspension sedimentation velocity is slower; Again the dispersivity test result is prone to disperse after showing the suspension jolting, does not lump; Suspension drug particles particle diameter accounts for 87.27% between 2.5～15 μ m persons; Account for 9.25% greater than 15 μ m persons; Meet the requirement of suspension injection.
2, stability test
Under the condition of (4500 ± 500) LX strong illumination 10d; Observing the appearance luster of doxycycline hydrochloride oil suspension of the present invention slightly deepens; The content decline scope of effective ingredient doxycycline is between 2.76%～7.70%; Do not detect catabolite, show that it is comparatively responsive to light, the suggestion shading is stored.30 ± 2 ℃ of temperature; Carry out 6 months accelerated tests under the condition of relative humidity 75 ± 5%, settling volume weighs favorable dispersibility than between 68.42%～71.85%; The content decline scope of effective ingredient doxycycline does not detect catabolite between 4.56%～6.13%.
3, safety evaluatio
Adopt Cavia porcellus and rabbit to carry out the outer hemolytic experimental study of systemic administration anaphylaxis, muscle local irritation and rabbit red cell body of doxycycline hydrochloride oil suspension respectively, with the LD of improvement karber's method to mice
50Measure.The result shows that these article do not have systemic anaphylaxis, the rabbit administered intramuscular is not had obvious local irritation, tame rabbit erythrocyte is not had external hemolytic Cavia porcellus; Each item safety that shows the doxycycline hydrochloride oil suspension is all good, for practical application provides strong technical foundation.
4, pharmacokinetics test
20% doxycycline hydrochloride oil suspension with embodiment 1 is an example.Select 9 health pig for use, by quiet notes 5% doxycycline injection of 3 cycle cross-over design, intramuscular injection 10% doxycycline injection and intramuscular injection 20% doxycycline hydrochloride oil suspension, dosage is 10mg/kg b.w..Time point by design is taken a blood sample; Adopted 0.01mol/L oxalic acid-acetonitrile-methanol (50: 35: 15; V/V/V) be mobile phase, the detection wavelength is 345nm, and flow velocity is 1.0mL/min; The concentration of doxycycline in the reversed-phase high-performance liquid chromatography ultraviolet detection blood plasma presents good linear relationship in 0.1～15 μ g/mL concentration range.Data when adopting 3P97 pharmacokinetics program software analyzing and processing medicine draw the related drugs kinetic parameter and see shown in the table 1.
Table 1
The main pharmacokinetic parameters of intramuscular injection 10% doxycycline injection and 20% doxycycline hydrochloride oil suspension
It is visible relatively to go up table, and the doxycycline hydrochloride oil suspension is in to absorb in the pig body than normal injection and is slowed down, and elimination is slowed down, and peak time postpones, and peak concentration reduces, and it is more extensive to distribute, and has long-acting slow-release effect extremely significantly.
5, clinical practice test
20% doxycycline hydrochloride oil suspension with embodiment 1 is an example.
Select laboratory to make a definite diagnosis 36 pigs that infect eperythrozoonosis, press 10mg/kg body weight intramuscular injection doxycycline hydrochloride oil suspension, 2 days once; Twice of successive administration; Clinical symptom disappearance such as rubescent, the jaundice of Corii Sus domestica skin, anemia after the administration, body temperature drops to normally, and pig feed is desired normal; More a week is observed in the back does not have recurrence, and cure rate reaches 97.2%.
Select laboratory to make a definite diagnosis 48 pigs that infect mycoplasma; Press 10mg/kg body weight intramuscular injection doxycycline hydrochloride oil suspension, 2 days once, twice of successive administration; Pig breathes after the administration, respiratory symptom such as cough disappears; Body temperature, appetite recover normal, and more a week is observed in the back does not have recurrence, and cure rate reaches 95.8%.
Claims (2)
1. oil suspension that is applied to treat the doxycycline hydrochloride of swine eperythrozoonosis or mycoplasma is characterized in that every liter doxycycline hydrochloride oil suspension comprises each component of following weight:
Doxycycline hydrochloride crude drug: 50～300g;
Suspending agent: 1～50g;
Surfactant: 1～30g;
Antioxidant: 0.1～2g;
Oil phase: add to 1 liter;
Said oil phase is the mixture of one or more any ratios of soybean oil, Oleum Gossypii semen, Oleum Arachidis hypogaeae semen, Oleum Sesami, Semen Maydis oil, Oleum Camelliae, Oleum Helianthi, Oleum Ricini or olive oil;
Described suspending agent comprises carboxymethyl cellulose (sodium), methylcellulose, arabic gum, xanthan gum, polyvinylpyrrolidone, the molecular weight mixture greater than one or more any ratios of 1000 Polyethylene Glycol, castor oil hydrogenated or aluminum monostearate;
Said surfactant comprises the mixture of one or more any ratios of lecithin, soybean phospholipid, fatty glyceride, sucrose fatty acid ester, polyoxyethylene sorbitan fatty acid ester, sorbitan fatty acid ester, polyoxyethylene fatty acid ester or polyoxyethylene aliphatic alcohol ether;
Said antioxidant is the mixture of one or more any ratios of gallic acid and esters, butylated hydroxyarisol, dibenzylatiooluene, tocopherol or ascorbyl palmitate.
2. the method for preparing of the said doxycycline hydrochloride of claim 1; It is characterized in that proportionally weighing doxycycline hydrochloride crude drug, suspending agent, surfactant, antioxidant and oil phase; Under aseptic condition,, promptly get the oil suspension of doxycycline hydrochloride through the colloid mill mix homogeneously.
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| CN101862293B true CN101862293B (en) | 2012-02-29 |
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Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103211827B (en) * | 2013-04-11 | 2014-11-26 | 黑龙江省汇丰动物保健品有限公司 | Compound amoxicillin oil suspension prescription and preparation method thereof |
| CN103536530A (en) * | 2013-10-30 | 2014-01-29 | 王玉万 | Doxycycline hydrochloride long-acting injection and preparation method |
| CN103705453B (en) * | 2014-01-07 | 2017-03-22 | 王玉万 | Oily injection containing doxycycline hydrochloride/poloxamer drug-loading particles |
| CN104288162B (en) * | 2014-05-29 | 2016-08-31 | 郑州百瑞动物药业有限公司 | A kind of milch cow doxycycline hydrochloride uterus injectant and preparation method thereof |
| CN106309365A (en) * | 2016-10-14 | 2017-01-11 | 成都乾坤动物药业股份有限公司 | Cefalexin oil suspension and preparation method thereof |
| CN107837241A (en) * | 2017-11-03 | 2018-03-27 | 河南益华动物药业有限公司 | A kind of retens micro-capsule and preparation method thereof |
| CN109846934B (en) * | 2018-11-21 | 2021-04-23 | 华南农业大学 | Veterinary eucalyptus oil doxycycline hydrochloride self-microemulsion and preparation method and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3674859A (en) * | 1968-06-28 | 1972-07-04 | Pfizer | Aqueous doxycycline compositions |
| CN1517090A (en) * | 2003-01-20 | 2004-08-04 | 王玉万 | Animal use suspensoid injection or emulsion containing antibacterial medicine |
| CN101703776A (en) * | 2009-09-28 | 2010-05-12 | 洛阳惠中兽药有限公司 | Method for preparing anti-infective agent long-acting injection |
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2010
- 2010-06-22 CN CN2010102075358A patent/CN101862293B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3674859A (en) * | 1968-06-28 | 1972-07-04 | Pfizer | Aqueous doxycycline compositions |
| CN1517090A (en) * | 2003-01-20 | 2004-08-04 | 王玉万 | Animal use suspensoid injection or emulsion containing antibacterial medicine |
| CN101703776A (en) * | 2009-09-28 | 2010-05-12 | 洛阳惠中兽药有限公司 | Method for preparing anti-infective agent long-acting injection |
Non-Patent Citations (1)
| Title |
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| 刘辉旺等.多西环素研究进展.《兽医导刊》.2008,(第1期),27-29. * |
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