CN1354754A - Injectable anthelmintic formulation - Google Patents
Injectable anthelmintic formulation Download PDFInfo
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- CN1354754A CN1354754A CN99815366A CN99815366A CN1354754A CN 1354754 A CN1354754 A CN 1354754A CN 99815366 A CN99815366 A CN 99815366A CN 99815366 A CN99815366 A CN 99815366A CN 1354754 A CN1354754 A CN 1354754A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
Abstract
Disclosed is an injectable anthelmintic formulation. The formulation includes a water-insoluble anthelmintic, a surfactant, cosolvent, water-soluble solvent and additives.
Description
The cross reference of related application
The application is to be the application of 98-50135 based on the application number of submitting korean industrial property office on November 23rd, 1998, and the content of described application is incorporated herein by reference.
Background of invention
(a) invention field
The present invention relates to a kind of injectable anthelmintic formulation, relate more specifically to the injectable anthelmintic formulation that a kind of active substance water-soluble and bioavailability has increased.
(b) description of related art
As everyone knows, ivermectin (or avermectins) is highly effective to inner and epizoon, described parasite parasitizes various Mammalss, comprise (R.W.Burg such as ox, pig, horse, et al., Antimicrobial Agents and Chemotherapy (1979) 361-367; J.C.Chabala, etal., J.Med.Chem. (1980) 23,1134-1136; J.A.Lasota, et al., Annu.Rev.Entimol. (1991) 36,91-117).
In order to increase the stability and the solvability of ivermectin (or avermectins), a lot of injectable preparations have now been developed and have used.Wherein two kinds of representational preparations hereinafter will be described.
In the U.S. Pat 4389379 of authorizing Lo and Williams, with nonionogenic tenside such as polysorbate80 (Tween 80) ivermectin is dissolved in the water, and, make resulting stabilized with mixtureization with cosolvent such as Sericosol N, propylene glycol, glycerine or polyoxyethylene glycol and matrix such as phenylcarbinol, lignocaine, p-Hydroxybenzoate or choline.According to this patent, can make ivermectin stabilization in the aqueous solution.But this patent is not described this ivermectin preparation pharmacokinetics and effect in animal body.
In addition, in the European patent EP 535734A1 that authorizes Chen and Williams,, increase the ivermectin time length in animal body up to 42 days with nonaqueous carrier such as hydrogenated castor oil or triacetin.But because said preparation is the oil base solution rather than the aqueous solution, the viscosity of this solution is near 500cps (centipoise; Record under 25 ℃ and 60rpm with the Brookfield viscometer that has the 2# spindle), be higher than typical ivermectin viscosity in aqueous solution widely.Therefore, the main drawback of this European patent is that filtration difficulty and syringeability are poor.At the other problems that preparation may run into during this preparation, comprise needed high power when mixing this solution with 400 to 4000rpm high rotating speed.
When using non-aqueous solution as injection formulations, the stability of ivermectin and solubility problem can solve, but can run into following point: the viscosity height; Syringeability is poor; Injection place may produce tissue injury or stimulation; Active ingredient is in the precipitation of injection zone.
Therefore, need better water-based injection formulations, in this preparation, a kind of in water-insoluble insect repellent ivermectin or the avermectins is not only solublely, stable, and can be absorbed rapidly and efficiently in animal body.
Summary of the invention
The purpose of this invention is to provide a kind of injectable anthelmintic formulation, the bioavailability that described preparation has the water-soluble of height and increased.
Another object of the present invention provides a kind of injectable anthelmintic formulation, and described preparation has absorption rate and the assimilated efficiency that has strengthened.
These two and other purpose can realize by a kind of injectable anthelmintic formulation.Described injection anthelmintic formulation comprises water-insoluble insect repellent, tensio-active agent, cosolvent and water miscible solvent.Said preparation may further include additive such as oxidation inhibitor and sanitas.Described tensio-active agent comprises the segmented copolymer of ethylene oxide and propylene oxide.
The accompanying drawing summary
That introduced and constitute the accompanying drawing of a specification sheets part, illustrate embodiments of the invention with specification sheets, and be used for explaining principle of the present invention.
Fig. 1 is comparison preparation of the present invention and commercially available Ivomee (U.S. Merck ﹠amp in pig; The graphic representation of pharmacokinetics Co.INC.).
Detailed Description Of The Invention
The invention provides a kind of injectable anthelmintic formulation of novelty. Described preparation comprises water-insoluble anthelmintic, surfactant, cosolvent and water miscible solvent. Said preparation may further include additive such as antioxidant and anticorrisive agent.
Water-insoluble anthelmintic as in the preparation of the present invention can use ivermectin or avermectins, perhaps their derivative. The ivermectin or the avermectins that comprise 0.5 to 2.0 (w/v) in the preparation, perhaps their derivative.
In preparation of the present invention, surfactant and cosolvent play solubilizer. In other words, surfactant and cosolvent make water-insoluble anthelmintic be easy to be dissolved in the water miscible solvent.
Described tensio-active agent can be the water solubility copolymer of listing in the pharmacopeia.Water solubility copolymer is possess hydrophilic property but also have hydrophobicity not only.This water solubility copolymer comprises the segmented copolymer of propylene oxide (PO) and ethylene oxide (EO).Described segmented copolymer has (EO)
x(PO)
y(EO)
xStructural unit, wherein the ratio of x and y is 0.75-2.0.Making this molecular-weight average is that the multipolymer of 9000-20000Da is dissolved in water before use in advance.The concentration of multipolymer in water is 5-25%.If the concentration of multipolymer surpasses 25%, then the viscosity of mixing solutions increases, and solvability may descend; Otherwise if its concentration is lower than 5%, the stability of so resulting injection formulations can't guarantee.
Described cosolvent can be alcohol, more preferably ethanol.The concentration of cosolvent in preparation of the present invention is 1-50% (w/v).If the concentration of cosolvent surpasses 50% (w/v), then animal can be felt pain, and the stability of resulting injection formulations reduces; On the contrary, if its concentration is lower than 1% (w/v), then be difficult to make water-insoluble insect repellent to be dissolved in the water miscible solvent.
Described water-soluble solvent can be a water.
In addition, preparation of the present invention can comprise various additives, as oxidation inhibitor and sanitas.For example, can make oxidation inhibitor, make sanitas with the phenylcarbinol of 0.5-10% (w/v) with the Yoshinox BHT (BHT) of 0.001-0.5% (w/v).
In order to prepare preparation of the present invention, can use substep hybrid system or direct mixing method.
In the substep hybrid system, ivermectin or avermectins are dissolved in the solvent that has added additive rapidly.Then this solution is added in another aqueous solution that has dissolved tensio-active agent in advance, makes injection formulations of the present invention thus.In direct mixing method, all components of preparation mixes simultaneously, makes injection formulations of the present invention.
Preferred substep hybrid system, because the expelling parasite medicament can be dissolved in the solvent at short notice fully, and other direct mixing method needs the time more than 24 hours, and the expelling parasite medicament is dissolved fully.
In these two kinds of methods, the pH of solution all is adjusted to 6.8-7.4, and water is suitably adjusted each component concentrations of injection formulations simultaneously, to be suitable for injection.At last, make the prepared solution sterilization by filtration.
The injection formulations of the present invention that makes according to aforesaid method, the maintenance under 4 ℃ and room temperature is stable to surpass 1 year, never is separated or precipitates.
Preparation of the present invention and the Ivomec (U.S. Merck ﹠amp that is purchased; Co. company) pharmacokinetics with pig studies show that, the absorption rate of preparation of the present invention reaches required blood concentration approximately than the fast twice of the absorption rate of described Ivomec.But preparation of the present invention and described Ivomec show similar degradation model.That is to say that the blood concentration of ivermectin all dropped to identical level under two kinds of situations in 4-5 days, and did not detect the significant difference between these two kinds of solution thereafter.
Because the physics and the pharmacokinetic performance of injection formulations of the present invention, can change according to the variation of composition of the present invention, therefore, need the variation of alcohol concn in the test preparation of the present invention to the solvability of ivermectin, the viscosity of preparation and the influence of ivermectin pharmacokinetics.The result shows, the concentration of ethanol height, and the solvability of ivermectin and the viscosity of preparation just increase.In addition, pharmacokinetics character also changes according to the variation of alcohol concn in the preparation.But, to compare with Ivomec, the variation of this pharmacokinetics character is not very big.
In a word, for preparation of the present invention, the retention time of ivermectin in blood is almost identical with Ivomec after measured, but the specific absorption Ivomec of ivermectin of the present invention early takes place 1 day, and the assimilated efficiency of preparation of the present invention roughly is the twice of Ivomec.In addition, also observe animal subject any unusual variation is not experienced in the increase of ivermectin assimilated efficiency.In other words, in animal subject, do not observe any toxicity or other side effect that the high assimilated efficiency because of ivermectin causes.These characteristics show that consumingly injection formulations of the present invention is more superior than prior art, and this can judge by its pharmacokinetic data that has improved.
In order to confirm that preparation of the present invention in the body and verminal effect, compares with Ivomec, carry out efficacy test.Use each boar, comprise piggy, store pig and sow, these pigs through the artificial challenge roundworm (Ascaris suum) and whipworm (Trichuris suis) (endoparasite), and itch mite (Sarcoptes scabiei) (vermin).Test shows that preparation of the present invention is identical with Ivomec or more superior than Ivomec.
More specifically, after Ivomec handled for 2 weeks, the parasitic ovum positive rate of store pig just reduced to 0%, and uses preparation of the present invention only to need for 1 week.For artificial challenge's store pig, after insect repellent treatment 1 week of beginning, the positive rate of parasitic ovum is as follows: in untreated group, and roundworm 86%, whipworm 57%; In the group of Ivomec treatment, roundworm 80%, whipworm 0.0%; In the group of preparation for treating of the present invention, roundworm 50%, whipworm 20%.In two groups of treatment groups, these percentage number averages reduce to 0.0% after 2 weeks.Behind preparation for treating of the present invention 1-3 days, discharge dead parasite; With the Ivomec treatment, then need 1-8 talent can observe dead parasite.This is the another good illustration that shows the present invention's good characteristic aspect the expeling endoparasite.
Simultaneously, also the expeling of piggy endoparasite is tested.In the untreated group, tetter pathological change rate rises to 1.67 by 0.58 after 1 week of on-test, and further rises to 4.20 after 3 weeks.But for the piggy through preparation for treating of the present invention, the tetter pathological change rate after 1 week falls sharply to 0.07 by 1.82, and remains 0.13 after 3 weeks; These change and the velocity of variation under Ivomec treatment situation: 1.06,0.13 and 0.07 is quite similar.
Shown in above-mentioned test, as wormer, preparation of the present invention is suitable with Ivomec at least, perhaps superior than Ivomec aspect pharmacokinetics and effect.And as described above such, can stably there be considerable time in this preparation at aqueous phase, and any physical change does not take place, as phase-splitting or precipitation.
To the present invention be described in further detail by following embodiment below.But the present invention can use in many ways, thereby is not subject to the following examples.
I. prepare injectable ivermectin solution with direct mixing method
[embodiment 1]
2ml phenylcarbinol (Pharmacopoeia Coreana level) is added in the flask of 300ml, and this flask was sterilized 30 minutes in advance at 121 ℃.The BHT (butylated hydroxytoluene, Pharmacopoeia Coreana level) that in this flask, adds following material: 0.01g then at once; 10ml ethanol (Pharmacopoeia Coreana level); 70ml water; 1.17g ivermectin; The Poloxamer 407 of 10g (German BASF).Subsequently, add the magnetic stirring bar of 5cm, with the speed stirring of 300-400rpm.
Resulting mixture begins to become clear and produces bubble, after approximately stirring 24 hours, obtains complete clear soln.Next step, in solution, add an amount of water (amount by needed final solution volume adds) to finish mixing process, and solution carried out vacuum filtration, and use the filter paper (U.S. Wattman filter paper) of 0.2 μ, make the ivermectin injection liquid of 1% (w/v) of abundant sterilization thus.Viscosity under the gained solution room temperature is 69cps (centipoise; Brookfield viscometer #CP-42 spindle, 6rpm).
[embodiment 2]
With the method identical with embodiment 1, preparation ivermectin injection liquid, the ivermectin that only is to use is 1% (w/v), Poloxamer 407 is 10.0% (w/v), and ethanol is 20.0% (w/v), and BHT is 0.01% (w/v), phenylcarbinol is 2.0% (w/v), and surplus is a water.
[embodiment 3]
With the method identical with embodiment 1, preparation ivermectin injection liquid, the ivermectin that only is to use is 0.5% (w/v), Poloxamer 407 is 10.0% (w/v), and ethanol is 15.0% (w/v), and BHT is 0.01% (w/v), phenylcarbinol is 2.0% (w/v), and surplus is a water.
[embodiment 4]
With the method identical with embodiment 1, preparation avermectins injection liquid, the avermectins that only is to use is 1% (w/v), Poloxamer 407 is 10.0% (w/v), and ethanol is 15.0% (w/v), and BHT is 0.01% (w/v), phenylcarbinol is 2.0% (w/v), and surplus is a water.
[embodiment 5]
With the method identical with embodiment 1, preparation avermectins injection liquid, the avermectins that only is to use is 0.5% (w/v), Poloxamer 407 is 10.0% (w/v), and ethanol is 15.0% (w/v), and BHT is 0.01% (w/v), phenylcarbinol is 2.0% (w/v), and surplus is a water.
II. prepare injectable ivermectin solution with the substep hybrid system
[embodiment 6]
The first step: the Poloxamer 407 (German BASF) of 10g is added in the flask of 300ml, and this flask was sterilized 30 minutes in advance at 121 ℃, and then added 70ml water.Afterwards, the magnetic stirring bar of 5cm is transferred in the flask, and stirs with the speed of 300-400rpm.Continue to mix about 70 minutes, be dissolved in water fully, make clarifying first mixing solutions thus until Poloxamer 407.Use this first mixing solutions of filter paper filtering of 0.2 μ then, the viscosity under the first mixing solutions room temperature that finally obtains is about 9.75cps (centipoise; Brookfield viscometer #CP-42 spindle, 6rpm).
Second step: big about the mixing process of the first step after 30 minutes, carry out second and go on foot mixing process.2ml phenylcarbinol (Pharmacopoeia Coreana level) is added in the flask of 25ml, and this flask was sterilized 30 minutes in advance at 121 ℃, and BHT (Pharmacopoeia Coreana level), 10ml ethanol (Pharmacopoeia Coreana level) and the 1.17g ivermectin of 0.01g is transferred in this flask.Afterwards, the magnetic stirring bar of 5cm is transferred in the flask, and stirs with the speed of 300-400rpm.Continue to mix about 10 minutes, till all the components dissolving in flask, make clarifying second mixing solutions thus.Use this second mixing solutions of filter paper filtering of 0.2 μ then.
The 3rd step: first mixing solutions and second mixing solutions are transferred in the sterilising vessel, mixed then about 10 minutes, obtain final mixing solutions.Afterwards, in final solution, add a spot of water (amount by needed final solution volume adds) and, make the ivermectin injection liquid of 1% (w/v) of abundant sterilization thus to finish mixing process.
[embodiment 7]
With the method identical with embodiment 6, preparation ivermectin injection liquid, the ivermectin that only is to use is 1.0% (w/v), Poloxamer 407 is 10.0% (w/v), and ethanol is 5.0% (w/v), and BHT is 0.01% (w/v), phenylcarbinol is 2.0% (w/v), and surplus is a water.
[embodiment 8]
With the method identical with embodiment 6, preparation ivermectin injection liquid, the ivermectin that only is to use is 0.5% (w/v), Poloxamer 407 is 20.0% (w/v), and ethanol is 10.0% (w/v), and BHT is 0.01% (w/v), phenylcarbinol is 2.0% (w/v), and surplus is a water.
[embodiment 9]
With the method identical with embodiment 6, preparation avermectins injection liquid, the avermectins that only is to use is 1.0% (w/v), Poloxamer 407 is 10.0% (w/v), and ethanol is 15.0% (w/v), and BHT is 0.01% (w/v), phenylcarbinol is 2.0% (w/v), and surplus is a water.
[embodiment 10]
With the method identical with embodiment 6, preparation avermectins injection liquid, the avermectins that only is to use is 0.5% (w/v), Poloxamer 407 is 10.0% (w/v), and ethanol is 15.0% (w/v), and BHT is 0.01% (w/v), phenylcarbinol is 2.0% (w/v), and surplus is a water.
Prepared injection formulations in the foregoing description carries out hereinafter described various tests.
[test 1] injection formulations of the present invention and Ivomec (U.S. Merck ﹠amp; Co. company)
The pharmacokinetics simultaneous test
According to the method for embodiment 6, the preparation injection formulations.It comprises 1.0% ivermectin, 10.0% Poloxamer 407,15.0% ethanol, 2.0% phenylcarbinol, 0.01% BHT, and surplus is an aqua sterilisa.Preparation of the present invention and Ivomec are injected to two groups of independent store pig test group, and dosage is every kg body weight 300 μ g.Then, by predetermined each time blood sample collection.Make described blood sample with the speed centrifugation of 3000rpm 20 minutes,, afterwards, blood plasma is stored under-20 ℃ to isolate the blood plasma in the blood.In order to analyze this two kinds of pharmacokinetics that are used for the test preparation of pig, two kinds of plasma samples are thawed, and with the improvement Montigny fluorescence derive-(J.Pharm.Biomed.Anal. (1990) 8,507-511) chemically examine for the HPLC analytical method.
In every kind of plasma sample of 1ml, add after the acetonitrile of 1ml, make resulting mixture with the speed centrifugation of 3000rpm 10 minutes.Then the supernatant liquor that obtains is carried out Solid-Phase Extraction.That is, in Solid-Phase Extraction, handle sample with Sep-Pak C18 cartridge case (U.S. Waters).Treat cartridge case with behind the nitrogen complete drying, with the sample of purifying wash-out at leisure, use nitrogen drying then with the 5ml chloroform.
Subsequently, with the 1-Methylimidazole of 100 μ l: acetonitrile (1: 2, v/v) mixture makes every kind of exsiccant sample dissolution, and to the trifluoroacetic anhydride that wherein adds 150 μ l: acetonitrile mixture (1: 2, v/v), cause isolating ivermectin to derive out, so that measure better.Then, get this derivative solution 100 μ l, analyze with the HPLC that has fluorimetric detector (TSP F3000, the U.S.) (TSO P1000, the U.S.).Peak value measurement is to carry out in the condition of the emission wavelength of the excitation wavelength of 374nm and 475nm.Volume ratio with 0.2% is the moving phase that acetate-methyl alcohol-acetonitrile mixture of 4: 32: 64 is done Nova-Pak C18 (4 μ, 3.6 * 150mm, Waters, the U.S.), and the flow velocity of moving phase is 1.5ml/ minute.
By the HPLC peak area of plasma sample and the comparison of typical curve, determine the concentration of ivermectin in the sample, described plasma sample is from the pig of having injected preparation of the present invention and Ivomec, described typical curve be by with 0.5,5 and the ivermectin (Sigma, the U.S.) of 50ng be added in the blood plasma of the pig that any insect repellent of no use handles and preparation.The processing of sample and measurement are carried out simultaneously, do not have any delay, and take from each blood sample all analyses immediately of a pig.In order to reduce the variation error in the sample preparation, when analyzing, standard model will prepare and use simultaneously at every turn.
At this moment, deutero-ivermectin B1a derivative goes out the peak when about 10 minutes HPLC retention time.Simultaneously a small peak occurred in the time of about 8 minutes, ivermectin B1b derivative is represented at this peak.
The measuring method of ivermectin concentration is in the blood sample, and these two peak area sums are compared with the ivermectin peak area sum in the typical curve.When analyzing, all pass through the serum sample of the ivermectin preparation standard of adding different concns, and the serum sample of this standard is handled by the treatment process identical with sample.Determine the concentration of sample with these freshly prepd standard models.
Typical curve equation (equation of linear regression) between ivermectin concentration and the HPLC peak area is: area=1.729 * 10
-4* ivermectin concentration+0.10039; Linear regression coeffficient (R
2) be 0.998.Determine ivermectin concentration in the blood sample with this linear equation, and be shown among Fig. 1 about the measurement result of preparation of the present invention and Ivomec.
As shown in the figure, injected the peak concentration of ivermectin in the porcine blood plasma sample of preparation of embodiment 6 preparations, than the peak concentration of ivermectin in the porcine blood plasma sample of having injected Ivomec higher 2 times.But, spent 4 or 5 days after the injection, the ivermectin concentration of preparation of the present invention and Ivomec all is reduced to equal level basically.
The reason of this different ivermectin pharmacokinetics is the difference on the composition of Ivomec and preparation of the present invention.Compare with Ivomec, preparation of the present invention absorbs quickly and enters blood, thereby demonstrates more superior pharmacokinetic performance.This is hinting that when using the ivermectin of same amount, the parasitic ability of killing of preparation of the present invention is better than Ivomec significantly.
[test 2] injection formulations of the present invention and other contain the ivermectin commodity
The syringeability simultaneous test
With injection formulations of the present invention (I), Ivomec (Merck Co.) (II), Ivomec-F (Merck Co.) (III), Baymec (Bayel Co.) (IV), Abamec (Daesung, Korea S) (V) and Dectomax (Pfizer) (VI) carry out the syringeability simultaneous test.
The above-mentioned every kind of preparation of 3ml is transferred to (Korea S Green CrossPharmaceutical company in Greenject-5 (5ml) syringe, No. 23,1 "); with syringeability survey meter (Japanese AIKOH Engineering Co., Ltd; Test Stand Model-2252, the CPU Gauge Model 9500) mean value of syringeability relatively.These values are shown in the following table 1.As shown in Table, the syringeability value of Formulation II (Ivomec) is minimum, is 0.53kg; The syringeability value of preparation IV (Baymec) is the highest, is 1.73kg.The syringeability value of preparation of the present invention-preparation I is approximately between maximum and Schwellenwert.When in a word, injecting this preparation during common product on the market of needed power and injection needed power similar.
Table 1
| Preparation | ??I | ??II | ??III | ??IV | ??V | ??VI |
| Syringeability [kg] | ??0.96 | ??0.53 | ??0.81 | ??1.73 | ??1.27 | ??1.32 |
[test 3] Ivomec and the viscosity measurement that contains the preparation of the present invention of different concentration ethanol
We after deliberation the physical properties of preparation of the present invention, change as viscosity and solvability composition with particular components.For viscosity test, prepare the multiple preparation of the present invention that contains different ethanol concentration (5,10,15 and 20%) according to the method for embodiment 6.
With Brookfield viscometer (spindle #CP-42,6rpm, 25 ℃), measure the viscosity of preparation of the present invention and Ivomec.As shown in following table 2, the viscosity of preparation of the present invention increases with the increase of ethanol content.Reaching all components dissolving becomes the clear needed time and increases with the decline of alcohol concn.
Table 2
| Preparation type | ??Ivomec | Preparation of the present invention (ethanol content %) | |||
| ??5％ | ??10％ | ??15％ | ??20％ | ||
| Viscosity (cps *) | ??36.6 | ??39.9 | ??43.8 | ??55.4 | ??59.3 |
| *Cps centipoise (by the Brookfie/d viscometer, in spindle #CP-42,6rpm and 25 ℃ of following mensuration) | |||||
[test 4] Ivomec and the pharmacokinetics that contains the preparation of the present invention of different concentration ethanol
Preparation of the present invention and Ivomec according to embodiment 6 preparations inject to two independent growing-finishing pig test group, and dosage is every kg body weight 300 μ g.After the injection, press preset time blood sample collection at interval, and by the method described in [test 1], the variation of measuring ivermectin concentration in the blood.The results are shown in the following table 3.
As shown in Table, the average peak concentration of ivermectin is 1.7 to 2.1 times of Ivomec in the blood, and the appearance time of Ivomec is 36 hours, and the appearance time of preparation of the present invention is 2-5 hour, and this depends on alcoholic acid content in the preparation of the present invention.
Although in table 3, do not illustrate, go out after the peak, underspeeding of ivermectin concentration is associated with the increase of ethanol content in the preparation.When ethanol content is lower than 10%, underspeed almost identical with Ivomec of the ivermectin concentration of preparation of the present invention after 5 days.
Table 3
| Preparation | Maximum ivermectin blood concentration * | Reach the time (h) of peak concentration |
| ??Ivomec | ?????????1.0 | ???????36.0 |
| Preparation of the present invention (5% ethanol) | ?????????2.1 | ???????3.5 |
| Preparation of the present invention (10% ethanol) | ?????????2.0 | ???????4.0 |
| Preparation of the present invention (15% ethanol) | ?????????1.7 | ???????4.3 |
| Preparation of the present invention (20% ethanol) | ?????????1.9 | ???????5.3 |
| ?????????????????? *Maximum ivermectin blood concentration with respect to Ivomec | ||
As mentioned above, we can recognize that [test 1] is similar with the result of [test 5].That is to say that the absorption rate of preparation of the present invention is approximately higher 2 times than the absorption rate of Ivomec.In addition, slow than Ivomec of underspeeding of the ivermectin blood concentration of preparation of the present invention is so that the concentration hold-time of the ivermectin of preparation of the present invention in blood identical with Ivomec almost.These results represent, use the ivermectin of the Ivomec of equal amts, and preparation of the present invention can more effectively kill parasite (this is confirmed by [test 5]).
Because above-mentioned characteristic is not tested under the situation of using excess ethyl alcohol (above 20%), therefore preferred the use is lower than 20% ethanol in preparation of the present invention.
[test 5] Ivomec and the preparation of the present invention that contains different concentration ethanol
Antibody in and the vermin efficacy test
For the antibody endoparasite efficacy test, use the sow and the store pig that have infected roundworm and whipworm; For antibody epizoa efficacy test, use the piggy that has infected itch mite.Every pig has been injected Ivomec or preparation of the present invention (0.3mg/ kg body weight).According to the timetable on local pig farm, take food and hello water to test pig by normal pattern and quantity.Make 40 piggy artificial challenge roundworms (100 infectious ovum) and whipworm (100 infectious ovum).In two weeks, carry out two subinfections.After the artificial challenge, all to check any ovum of discharge every day.
Test-results is as described below.
(5-1) effect of store pig and safety testing
The test-results of artificial challenge's store pig shows that after one week of on-test, the parasitic ovum positive rate is as follows: preparation of the present invention is 0%; Ivomec is 17%; Untreated control group is 33%.After two weeks, the parasitic ovum positive rate of all pigs of handling with preparation of the present invention and Ivomec all becomes 0%, and the percentage ratio of control group rises to 50%.
For the pig of handling with Ivomec or preparation of the present invention, parasitic ovum be reduced to 100%; And the pig of undressed control group, its parasitic ovum be reduced to 0%.It is 0% that the pork chop of control group goes out extremely parasitic, and goes out the parasitic 23.3-26.7% that is with the pork chop that Ivomec or preparation of the present invention were handled.In addition, in the pig that all were handled, do not observe any injection zone unusual (as heating, inflammation) and dystropy.
</entry></row></tbody></tgroup></table></tables>
(5-2) efficacy test of carrying out with artificial challenge's store pig
In the pig of having injected preparation of the present invention, observed dead parasite between first day and the 3rd day and discharged, and pig dead parasite of discharge between first day and the 8th day after the processing of having injected Ivomec.Wormer was treated after 5 weeks, and all pigs are carried out the autopsy inspection, to examine the parasite that exists.In the small intestine of untreated pig, find some parasites, and in the pig of preparation for treating of the present invention, do not finding parasite.And in order to check the effect of preparation of the present invention to roundworm, about 1-5 week is carried out the artificial challenge with about 100 larvas to pig when handling and before handling.Do not find larva in test pig, this represents that preparation of the present invention can also kill this parasite effectively.
In addition, in test pig, do not observe injection zone unusual (as heating, inflammation) and dystropy.During autopsy is checked, do not detect any injection vestige or inflammation in injection zone.
Table 5
| Preparation * | The number of pig | Dead parasitic discharge | The autopsy check result |
| Preparation of the present invention | ????10 | Injection back 1-3 days | No parasite |
| Preparation of the present invention * 2 | ????10 | Injection back 1-3 days | No parasite |
| Ivomec | ????10 | Injection back 1-8 days | No parasite |
| Control group | ????7 | Do not have | 100% infects |
| *The injection volume of preparation of the present invention and Ivomec: the injection volume of 0.3mg/kg body weight preparation of the present invention * 2:0.6mg/kg body weight | |||
(5-3) efficacy test of the store pig of artificial challenge endoparasite-roundworm
Pig artificial challenge roundworm to three test group.During on-test, detect the roundworm egg of all pigs in each test group.But after the week, the roundworm egg positive rate of undressed control group pig is 86%, is 40-50% with the roundworm egg positive rate of preparation treatment group pig of the present invention, and the roundworm egg positive rate of the group pig of handling with Ivomec is 80%.Between second week and the 5th week, the roundworm egg positive rate of control group is 86-100%, and the roundworm egg positive rate of the group of handling through Ivomec or preparation of the present invention is 0%, this means all parasites all be killed (seeing Table 6).
Table 6
| Preparation * | The number of pig | Roundworm egg positive rate (%) | Roundworm egg decrement (%) | |||||
| 0 week | 1 week | 2 weeks | 3 weeks | 4 weeks | 5 weeks | |||
| Preparation of the present invention | 10 | 100 | 40 | 0 | 0 | 0 | 0 | ????100 |
| Preparation of the present invention * 2 | 10 | 100 | 50 | 0 | 0 | 0 | 0 | ????100 |
| Ivomec | 10 | 100 | 80 | 0 | 0 | 0 | 0 | ????100 |
| Control group | 7 | 100 | 86 | 100 | 86 | 86 | 86 | ????0 |
| *The injection volume of preparation of the present invention and Ivomec: the injection volume of 0.3mg/kg body weight preparation of the present invention * 2:0.6mg/kg body weight | ||||||||
The ight soil of check test pig, observe: the roundworm egg number of every gram ight soil when on-test (EPG, roundworm egg number/gram) is 100-10560.In these pigs of handling with Ivomec or preparation of the present invention, detected parasitic ovum descends after several first weeks significantly from ight soil, has just detected less than parasitic ovum after two weeks.But, in the pig of control group, can also continue to observe parasitic ovum.The results are shown in the following table 7 of this test.
Table 7
| Preparation * | The number of pig | Test subject ** | |||||
| EPG (roundworm/whipworm) | |||||||
| 0 week | 1 week | 2 weeks | 3 weeks | 4 weeks | 5 weeks | ||
| Preparation of the present invention | ?10 | ??778±1053 | ??52±69 | ??0±0 | ??0±0 | ??0±0 | ??0±0 |
| Preparation of the present invention * 2 | ?10 | ??2156±3095 | ??99±120 | ??0±0 | ??0±0 | ??0±0 | ??0±0 |
| Ivomec | ?10 | ??4188±3025 | ??168±198 | ??0±0 | ??0±0 | ??0±0 | ??0±0 |
| Control group | ?10 | ??2069±1121 | ??971±551 | ??1058±904 | ??483±348 | ??248±216 | ??410±374 |
| *The injection volume of preparation of the present invention and Ivomec: the injection volume of 03mg/kg body weight preparation of the present invention * 2:0.6mg/kg body weight **Collect 1-2g ight soil, with MacMaster egg count case counting parasitic ovum number, with this number divided by the ight soil amount | |||||||
(5-4) efficacy test of the store pig of artificial challenge endoparasite-whipworm
Pig artificial challenge whipworm to three test group.During on-test, the whipworm ovum positive rate is 29-100%.After one week, the whipworm ovum positive rate that records undressed control group is 57%, and the whipworm ovum positive rate of the group of handling with preparation of the present invention is 20%, and the whipworm ovum positive rate of the group of handling with Ivomec is 0%.In the 2nd thoughtful the 5th week after handling, the whipworm ovum positive rate of control group is 0-86%, and through the group of Ivomec or preparation of the present invention processing, does not all detect whipworm.Below table 8 listed the result of this test.
Table 8
| Preparation * | The number of pig | Whipworm ovum positive rate (%) | Whipworm ovum decrement (%) | |||||
| 0 week | 1 week | 2 weeks | 3 weeks | 4 weeks | 5 weeks | |||
| Preparation of the present invention | 10 | 90 | 20 | 0 | 0 | 0 | 0 | ???100 |
| Preparation of the present invention * 2 | 10 | 100 | 20 | 0 | 0 | 0 | 0 | ???100 |
| Ivomec | 10 | 60 | 0 | 0 | 0 | 0 | 0 | ???100 |
| Control group | 7 | 29 | 57 | 86 | 29 | 0 | 0 | ???0 |
| *The injection volume of preparation of the present invention and Ivomec: the injection volume of 0.3mg/kg body weight preparation of the present invention * 2:0.6mg/kg body weight | ||||||||
The ight soil of check test pig simultaneously.From every gram ight soil, detect 0-215 whipworm ovum (EPG, ovum/gram).To the 3rd when week, also from the ight soil of control group, detect whipworm ovum, and for the group of handling through Ivomec or preparation of the present invention, after the week, the whipworm ovum number just descends obviously, after two weeks, has just detected less than whipworm ovum.The results are shown in following table 9.
Table 9
| Preparation * | The number of pig | The test item ** | |||||
| EPG (roundworm/whipworm) | |||||||
| 0 week | 1 week | 2 weeks | 3 weeks | 4 weeks | 5 weeks | ||
| Preparation of the present invention | 10 | 113±68 | 34±59 | 0±0 | 0±0 | 0±0 | 0±0 |
| Preparation of the present invention * 2 | 10 | 113±25 | 29±49 | 0±0 | 0±0 | 0±0 | 0±0 |
| Ivomec | 10 | 72±77 | 0±0 | 0±0 | 0±0 | 0±0 | 0±0 |
| Control group | 10 | 25±56 | 53±77 | 174±259 | 98±218 | 0±0 | 0±0 |
| *The injection volume of preparation of the present invention and Ivomec: the injection volume of 0.3mg/kg body weight preparation of the present invention * 2:0.6mg/kg body weight **Collect 1-2g ight soil, with MacMaster egg count case counting parasitic ovum number, with this number divided by the ight soil amount | |||||||
(5-5) the verminal efficacy test of anti-piggy
Carry out the efficacy test of preparation antibody epizoa-itch mite of the present invention with piggy.In the control group of unprocessed piggy, the pathological change rate of skin is to increase to afterwards in 0.58, one week 1.67, three weeks further to increase to 4.20 afterwards when on-test.In the piggy group of handling through preparation of the present invention, the dermal pathology velocity of variation after the week further reduces to 0.13 after reducing to for 0.7, three week by 1.82.In the pig group of handling through Ivomec, the dermal pathology velocity of variation after the week further reduces to 0.07 after reducing to for 0.13, three week by 1.06.The results are shown in the table 10.
Table 10
| Preparation * | The number of pig | Weight (the kg of M ± SD) ** | Weight increase (0-3 week, kg) | Vermin pathology changes | ||||
| 0 week | 1 week | 3 weeks | 0 week | 1 week | 3 weeks | |||
| Preparation of the present invention | 15 | 7.6±1.17 | 9.5±0.89 | 14.2±1.54 | 6.6 | 1.82 | 0.07 | 0.13 |
| Preparation of the present invention * 2 | 15 | 6.4±0.82 | 8.4±0.92 | 12.7±1.30 | 6.3 | 1.79 | 0.31 | 0.17 |
| Ivomec | 15 | 6.6±0.64 | 8.6±0.88 | 12.6±1.95 | 6.0 | 1.06 | 0.13 | 0.07 |
| Control group | 15 | 5.3±0.52 | 6.9±0.73 | 11.0±0.74 | 5.7 | 0.58 | 1.67 | 4.20 |
| *The injection volume of preparation of the present invention and Ivomec: the injection volume of 0.3mg/kg body weight preparation of the present invention * 2:0.6mg/kg body weight **Carrying out measured body weight and vermin inspection M 0,1 and 3 weeks: weight in average; SD: standard deviation | ||||||||
(5-5) the interior and verminal efficacy test of anti-sow body
Carry out in the antibody of preparation of the present invention with sow and the vermin efficacy test.Do not find sow diarrhoea when 1,2 and 3 weeks.Inject after the preparation of the present invention 2 days, in the ight soil of sow, check out dead parasite, just checked after 7 days less than parasite.For the sow of injection Ivomec, 3 days begin to discharge afterwards parasite, have just no longer discharged after 8 days.In addition, for vermin, in the sow of preparation of the present invention or Ivomec processing, all parasites all are removed, and in undressed sow control group, do not find significantly to improve.
In addition, in all treated sows, do not observe injection zone unusual (for example, heating, inflammation) and dystropy.Also to the sow of the handling inspection of dissecting a body.Do not find any vestige and infection in injection zone.The results are shown in the following table 11 of this test.
</entry></row></tbody></tgroup></table></tables>
As mentioned above, preparation of the present invention is very stable at aqueous phase, does not produce to be separated.In addition, shown in a large amount of clinical trials, preparation of the present invention have pharmacokinetic performance preferably and with prior art quite or be better than in the antibody of prior art and verminal effect.Other physical and chemical performance of preparation of the present invention comprises longer stability, similar viscosity and syringeability, can be compared with prior art.And when using preparation of the present invention, do not find any physical damnification or other side effect in injection zone.
Although by preferred embodiment the present invention is described in detail, but person of skill in the art will appreciate that, under the situation of the spirit and scope of the present invention of in not breaking away from, being set forth, can make various modifications and replacement to the present invention as appended claims.
Claims (8)
1. injectable anthelmintic formulation comprises:
Water-insoluble insect repellent;
Tensio-active agent comprises the segmented copolymer of ethylene oxide (EO) and propylene oxide (PO);
Cosolvent; With
Water miscible solvent.
2. the preparation of claim 1, wherein said water-insoluble insect repellent is selected from avermectins, ivermectin and derivative thereof, and the content in said preparation is 0.5-2.0% (w/v).
3. the preparation of claim 1, the content of wherein said tensio-active agent in said preparation is 5-25% (w/v).
4. the preparation of claim 3, wherein said cosolvent is an ethanol, and the content of this cosolvent in preparation is 1-50% (w/v).
5. the preparation of claim 1 wherein further comprises additive.
6. the preparation of claim 5, wherein said additive comprises the Yoshinox BHT of 0.001-0.5% (w/v) and the phenylcarbinol of 0.5-10% (w/v).
7. the preparation of claim 1, wherein said segmented copolymer has (EO)
x(PO)
y(EO)
xStructural unit, the ratio of x and y is 0.75-2.0 here, and the molecular-weight average of this segmented copolymer is 9000-20000Da.
8. the preparation of claim 1, wherein said insect repellent are to be used for killing in the body and verminal.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR98/50135 | 1998-11-23 | ||
| KR1019980050135A KR100315465B1 (en) | 1998-11-23 | 1998-11-23 | Animal Insect Repellent Compositions Containing Water Soluble Polymer and Alcohol |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1354754A true CN1354754A (en) | 2002-06-19 |
| CN1166676C CN1166676C (en) | 2004-09-15 |
Family
ID=19559247
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB998153664A Expired - Fee Related CN1166676C (en) | 1998-11-23 | 1999-11-22 | Injectable anthelmintic formulation |
Country Status (7)
| Country | Link |
|---|---|
| KR (1) | KR100315465B1 (en) |
| CN (1) | CN1166676C (en) |
| AU (1) | AU753532B2 (en) |
| BR (1) | BR9915559A (en) |
| MX (1) | MXPA01005123A (en) |
| NZ (1) | NZ511852A (en) |
| WO (1) | WO2000031098A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103720652A (en) * | 2014-01-07 | 2014-04-16 | 王玉万 | Abamectin-drug-containing injection prepared from poloxamer and oily medium |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6319945B1 (en) * | 2000-06-29 | 2001-11-20 | L. Dean Parks | Method of treatment of seborrheic dermatitis |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4781924A (en) * | 1987-11-09 | 1988-11-01 | Alza Corporation | Transdermal drug delivery device |
| US5593683A (en) * | 1990-05-01 | 1997-01-14 | Mdv Technologies, Inc. | Method of making thermoreversible polyoxyalkylene gels |
| US5439924A (en) * | 1991-12-23 | 1995-08-08 | Virbac, Inc. | Systemic control of parasites |
| JPH07173017A (en) * | 1993-12-17 | 1995-07-11 | Toshio Suzuki | Composition for preventing pines from being damaged by death and method for prevention |
-
1998
- 1998-11-23 KR KR1019980050135A patent/KR100315465B1/en not_active IP Right Cessation
-
1999
- 1999-11-22 AU AU15844/00A patent/AU753532B2/en not_active Ceased
- 1999-11-22 CN CNB998153664A patent/CN1166676C/en not_active Expired - Fee Related
- 1999-11-22 MX MXPA01005123A patent/MXPA01005123A/en unknown
- 1999-11-22 WO PCT/KR1999/000704 patent/WO2000031098A1/en active IP Right Grant
- 1999-11-22 BR BR9915559-1A patent/BR9915559A/en not_active IP Right Cessation
- 1999-11-22 NZ NZ511852A patent/NZ511852A/en unknown
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103720652A (en) * | 2014-01-07 | 2014-04-16 | 王玉万 | Abamectin-drug-containing injection prepared from poloxamer and oily medium |
Also Published As
| Publication number | Publication date |
|---|---|
| KR20000033304A (en) | 2000-06-15 |
| CN1166676C (en) | 2004-09-15 |
| AU1584400A (en) | 2000-06-13 |
| BR9915559A (en) | 2001-11-20 |
| MXPA01005123A (en) | 2002-06-04 |
| WO2000031098A1 (en) | 2000-06-02 |
| KR100315465B1 (en) | 2002-02-19 |
| NZ511852A (en) | 2003-08-29 |
| AU753532B2 (en) | 2002-10-17 |
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