CN103251584A - Preparation of artemether/benflumetol compound fat emulsion for injection and application of artemether/benflumetol compound fat emulsion in malaria treatment - Google Patents
Preparation of artemether/benflumetol compound fat emulsion for injection and application of artemether/benflumetol compound fat emulsion in malaria treatment Download PDFInfo
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Abstract
The invention discloses an artemether/benflumetol compound fat emulsion preparation which contains 0.01-1.5 percent by weight of artemether, 0.01-3.5 percent by weight of benflumetol, 10.0-30.0 percent by weight of injection oil, 0.6-30.0 percent by weight of emulsifier, 0-10 percent by weight of solubilizer, 00.01-5 percent by weight of co-emulsifier, 2.25-7 percent by weight of isoosmolar agent, 0.002-0.075 percent of antioxidant and the balance of injection water. The invention further discloses a preparation method as well as pharmacodynamics and safety elevation of the artemether/benflumetol compound fat emulsion preparation. The artemether/benflumetol compound fat emulsion preparation has the characteristics of good biocompatibility, high physical stability, good safety, high medicament-loading capacity and the like and is convenient to prepare. An in-vivo pharmacodynamic animal experiment proves that the artemether/benflumetol compound fat emulsion preparation has a remarkably killing role in plasmodium and can be used for effectively controlling the relapse of the plasmodium. Meanwhile, the artemether/benflumetol compound fat emulsion preparation can be used for providing nutritions required for the body of a patient suffering from malaria, improving the lymphocyte activity and assisting the patient in resisting malaria and getting recovery.
Description
Technical field
The present invention relates to a kind of fat milk injection, particularly Artemether/benflumetol compound fat emulsified injection.Route of administration is intravenous injection or intramuscular injection.The preparation technology, prescription, purposes, pharmacodynamic study and the safety evaluatio that also relate to this Artemether/benflumetol compound fat emulsified injection.
Background technology
Arteannuin is that Chinese scholar is separated a kind of effective malaria monomer of purifying out in early 1970s from Herba Artemisiae Annuae, it is the sesquiterpene lactone compound that contains the peroxide bridge structure, have fast, efficient, no Drug resistance, hypotoxic characteristics, be called " maximum for the treatment of malaria is wished " by World Health Organization (WHO), can be considered China pharmacy worker to the maximum contribution of human society.Its discovery becomes world's malaria history another important mileage after quinine.But studies show that, take the arteannuin preparation for a long time separately protozoon is developed immunity to drugs, make compound formulation and arteannuin and other malaria medicine united, also can nearly 95% curative effect be arranged to non-concurrent malaria.Therefore, in February, 2004, the malaria treatment medication of WHO policy is reformed, and proposes to stop using artemisine folk prescription antimalarial drug, and advocate employing based on the combination medicine (Artemisinin-based combination therapies is called for short the ACTs therapy) of artemisinin-based drug.
At present, this combination medicine based on artemisinin-based drug mainly contains: Artemether-LUMEFANTRINE, artesunate-amodiaquine, artesunate-sulfamethoxine-pyrimethamine, artesunate-mefloquine, amodiaquine and sulfamethoxine-pyrimethamine drug combination etc., wherein the effect of Artemether-LUMEFANTRINE drug combination is best.This is because Artemether-LUMEFANTRINE drug combination can the potentiation complementation: the artemisinin derivatives Artemether has stronger killing action to the plasmodium schizont, and is evident in efficacy for multiple resistant malaria and anti-chloroquine pernicious malaria.But it exists action time short again, shortcomings such as relapse rate height.It is totally thorough that benflumetol is killed plasmodium, and effective percentage reaches more than 95%, and relapse rate is lower than 5%, but onset is slow.So will can overcome the high and slow shortcoming of benflumetol effect of Artemether relapse rate behind the two recurrence due to taking drug sides simultaneously.Have the control symptom fast, kill plasmodium thoroughly, the strain of antagonism worm effectively, advantage such as delay to develop immunity to drugs.And this compound recipe does not have cross tolerance with existing other antimalarial, and is easy to use, safe.This compound oral tablet has obtained the listing approval of U.S. FDA on April 8th, 2009.But at present, the compound recipe dosage form of Artemether and benflumetol has only oral formulations, discloses Artemether/benflumetol compound oral tablet, compound oral syrup, compound suppository etc. as " number of patent application is 90106722.9 Chinese patent "." number of patent application is 200610037383.5 Chinese patent " discloses the self-emulsifier of Artemether/benflumetol compound recipe." number of patent application is 200710057537.1 Chinese patent " discloses the drop pill of Artemether/benflumetol compound recipe." number of patent application is that 200710057538.6 Chinese patent discloses a kind of preparation method for the treatment of the benflumetol dripping pill of malaria ".These all are peroral dosage forms, when clinical use, can not be used for the emergency treatment of malaria, though they are at the oral administration biaavailability that has improved benflumetol in varying degrees simultaneously, but because the fatty dependency of benflumetol (be the influence that the oral absorption of benflumetol is subjected to food, eat food rich in fat when the patient takes medicine, just can have higher drug absorption rate and higher blood drug level to kill the malaria worm) make benflumetol when oral, need increase the clinical therapeutic efficacy that taking dose and number of times ensure medicine.So benflumetol dosage when clinical use even reaches 2880mg up to 1840mg, taking of so long-term high dose can be accelerated drug-fast generation, thereby shortens the service life of benflumetol greatly, reduces result of use.In addition from patient's angle, high dose, frequently take medicine and increase financial burden undoubtedly, in fact, the high main barrier that has become malaria patients' treatment at present of expense.In order to overcome above-mentioned defective, be necessary to develop the novel form of Artemether/benflumetol compound recipe.
Fat milk injection is a kind of new fat-soluble medicine carrier.It is to be main component with the soybean oil, is emulsifying agent with refined lecithin, and glycerol is isotonic agent, forms through high pressure homogenize.It has good biocompatibility, physical stability height, be convenient to preparation, characteristics such as safety is good, drug loading height, is very suitable for injection.Simultaneously, it can also improve malnourished patient's lymphocyte activity, for the patient provides nutrition, is highly suitable for the emergency treatment of subtertian malaria and general malaria.
In sum; in order to protect the clinical service life of Artemether and benflumetol; improve the bioavailability of Artemether/benflumetol compound recipe, the present invention discloses injection, preparation method, application, pharmacodynamics and the safety evaluatio of a kind of Artemether/benflumetol compound fat emulsion.
Summary of the invention
In order to improve the bioavailability of Artemether/benflumetol compound recipe, also in order to satisfy the demand that clinical emergency treatment, treatment cerebral malaria and pernicious malaria are used for injection, the invention provides a kind of Artemether/benflumetol compound injection is Artemether/benflumetol compound fat Emulsion.Owing to be injection, so its bioavailability is 100%.It need not to add any cosolvent when being used for injection, therefore reduced the incidence rate of toxic and side effects.And it can also improve patient's lymphocyte activity for malaria patients provide health required nutrition, helps the patient to resist malaria and rehabilitation.
The present invention also provides the preparation method of this Artemether/benflumetol compound fat emulsified injection.
The technical solution adopted for the present invention to solve the technical problems: a kind of Artemether/benflumetol compound fat emulsified injection, be characterized in containing the Artemether of 0.01～1.5wt%, 0.01 the benflumetol of～3.5wt%, 10.0 the oil for injection of～30.0wt%, the emulsifying agent of 0.6～30wt%, the solubilizing agent of 0～10wt%, 0.01 the co-emulsifier of～5wt%, 2.25 the isotonic agent of～7wt%, the vitamin E of 0.002～0.075wt%, all the other are water for injection;
Described oil for injection be in soybean oil, Oleum Camelliae, Oleum Sesami, median chain triglyceride oil, long chain triglycerides or the olive oil any or appoint several;
Described emulsifying agent is any in Ovum Gallus domesticus Flavus lecithin, soybean lecithin, hydrogenated yolk lecithin, hydrogenated soy phosphatidyl choline, the synthetic lecithin;
Described co-emulsifier be in Tween 80, F68, the oleic acid any or appoint several;
Described solubilizing agent is any of dehydrated alcohol, chloroform or isopropyl alcohol;
Described isotonic agent is any of glycerol, glucose or xylitol.
The preparation method of a kind of Artemether described above/benflumetol compound fat emulsified injection is characterized in may further comprise the steps:
(a) solubilizing agent of the benflumetol of the Artemether of 0.01～1.5wt% and 0.01～3.5wt% being put into 0～10wt% is fully after the dissolving, mix with the oil for injection of 10.0～30.0wt%, after high temperature evaporation is removed solubilizing agent, under nitrogen protection, add the emulsifying agent of 0.6～30wt% and the antioxidant of 0.002～0.075wt%, be heated to 40～80 ℃, form oil mixture;
(b) with the co-emulsifier of the isotonic agent of 2.25～7wt%, 0.01～5wt%, water for injection in 40～80 ℃ of mixing, form aqueous mixture;
(c) under nitrogen protection, aqueous mixture is mixed with oil mixture, at 40～80 ℃, after the high speed dispersion, regulate pH to 6.0～9.0 under 2000～18000r/min condition, be to carry out homogenizing under 70～110MPa condition 4～10 times at pressure, obtain uniform milky solution;
(d) step (c) gained milky solution filtered, lead to nitrogen-sealed, behind 100～125 ℃ of sterilization treatment 10～30min, storage below 25 ℃.
Described Artemether/benflumetol compound fat emulsified injection, its purposes is to treat malaria, comprises the rescue of every other day, three days, pernicious, ovum type, brain type, gastrointestinal type, too high pattern of fever, blackwater fever, pernicious malaria and critical malaria.
Described Artemether/benflumetol compound fat emulsified injection, its route of administration is intravenous injection or intramuscular injection.
The invention has the beneficial effects as follows: the Artemether/benflumetol compound fat emulsified injection of the inventive method preparation brings up to 100% with the bioavailability of Artemether/benflumetol compound recipe.And, can utilize the characteristic of fat milk inhibition growth of malaria parasites, nutrition supply, strengthen the antimalarial effect of Artemether/benflumetol, provide health required nutrition for malaria patients simultaneously, improve patient's lymphocyte activity, help the patient to resist malaria and rehabilitation.Artemether/benflumetol compound fat emulsion the intravenous injection of the inventive method preparation can be directly used in injection, does not need the hydrotropy carrier, thereby has reduced the toxic and side effects to human body, can increase stability of drug simultaneously.And the pharmacodynamics zoopery confirms in body: this preparation has tangible killing action to plasmodium, and can effectively control plasmodial recurrence.
Description of drawings
Fig. 1: through positive controls, AL-LE-1, AL-LE-2and AL-LE-3 tail vein injection treatment plasmodial growth tendency figure of P.berghei (n=3) after 3 days;
Fig. 2: contain plasmodium (A) in the mouse blood and turn out cloudy after do not contain the microphotograph of plasmodium (B).
Further specify the present invention below by embodiment.It should be understood that; the product of the embodiment of the invention and preparation method are only used for illustrating the present invention; rather than limitation of the present invention, the simple modifications to product of the present invention and preparation method under design prerequisite of the present invention all belongs to the scope of protection of present invention.Except as otherwise noted, " % " among the present invention all is quality criterias.
The specific embodiment
The present invention verifies the amount ranges of various adjuvants in the pharmaceutical formulation of injection Artemether/benflumetol compound fat emulsion.
One, the Artemether/benflumetol compound fat emulsified injection of different oil phase preparations
Embodiment 1:
Prescription:
10mg Artemether and 30mg benflumetol are put into the 2mL dehydrated alcohol fully be dissolved into solution; this solution is mixed with 10g injection soybean oil; the antioxidant vitamin E that adds 1.2g injection Ovum Gallus domesticus Flavus lecithin, 0.02g behind the dehydrated alcohol under nitrogen protection is removed in evaporation; in 60 ℃ of mixing, form oil mixture.50mL water for injection, 0.4g enuatrol and 2.5g glycerol in 60 ℃ of mixing, are formed aqueous mixture.Under nitrogen protection, aqueous mixture is mixed with oil mixture, and add water to 100mL, under 60 ℃, mechanical agitation 20min makes colostrum after the 6500r/min high speed dispersion, after regulating pH to 7.0, be homogenizing 8 times under the 105MPa condition at pressure, obtain uniform milky solution; Above-mentioned milky solution filters, logical nitrogen-sealed, and behind 115 ℃ of sterilization treatment 15min, storage is Artemether: benflumetol (1:3) compound fat emulsion below 25 ℃.
Embodiment 2:
Prescription:
120mg Artemether and 40mg benflumetol are put into the 4mL chloroform fully be dissolved into solution; this solution is mixed with 10g injection Oleum Camelliae; the antioxidant vitamin E that adds 1.2g soybean lecithin for injection, 0.02g behind the chloroform under nitrogen protection is removed in evaporation; in 70 ℃ of mixing, form oil mixture.70mL water for injection, 2.5g xylitol, 0.2g F68 in 70 ℃ of mixing, are formed aqueous mixture.Under nitrogen protection, aqueous mixture is mixed with oil mixture, add water to 100mL, under 70 ℃, mechanical agitation 20min makes colostrum after the 7000r/min high speed dispersion, after regulating pH to 7.5, be to carry out homogenizing under the 90MPa condition 9 times at pressure, obtain uniform milky solution; Above-mentioned milky solution filters, logical nitrogen-sealed, and behind 120 ℃ of sterilization treatment 25min, storage is Artemether: benflumetol (3:1) compound fat emulsion below 25 ℃.
Two, the Artemether/benflumetol compound fat emulsified injection of different emulsifiers preparation
Embodiment 3:
Prescription:
20mg Artemether and 100mg benflumetol are put into 6mL acetone fully be dissolved into solution; this solution is mixed with 20g injection Oleum Sesami; the antioxidant vitamin E that adds 2.4g injection Ovum Gallus domesticus Flavus lecithin, 0.02g behind the acetone under nitrogen protection is removed in evaporation; in 70 ℃ of mixing, form oil mixture.150mL water for injection, 5g glycerol, 0.02g oleic acid in 70 ℃ of mixing, are formed aqueous mixture.Under nitrogen protection, aqueous mixture is mixed with oil mixture, add water to 200mL, under 70 ℃, mechanical agitation 20min makes colostrum after the 7500r/min high speed dispersion, after regulating pH to 8.0, be to carry out homogenizing under the 95MPa condition 6 times at pressure, obtain uniform milky solution; Above-mentioned milky solution filters, logical nitrogen-sealed, and behind 125 ℃ of sterilization treatment 10min, storage is Artemether: benflumetol (1:5) compound fat emulsion below 25 ℃.
Embodiment 4:
Prescription:
20mg Artemether and 120mg benflumetol are put into the 3mL isopropyl alcohol fully be dissolved into solution; this solution is mixed with 30g injection median chain triglyceride oil; the antioxidant vitamin E that adds 1.2g injection hydrogenated yolk lecithin, 0.02g behind the isopropyl alcohol under nitrogen protection is removed in evaporation; in 60 ℃ of mixing, form oil mixture.50mL water for injection, 2.5g glycerol, 0.4g F68 in 70 ℃ of mixing, are formed aqueous mixture.Under nitrogen protection, aqueous mixture is mixed with oil mixture, add water to 100mL, under 70 ℃, mechanical agitation 15min makes colostrum after the 8000r/min high speed dispersion, after regulating pH to 8.0, be to carry out homogenizing under the 100MPa condition 8 times at pressure, obtain uniform milky solution; Above-mentioned milky solution filters, logical nitrogen-sealed, and behind 100 ℃ of sterilization treatment 30min, storage is Artemether: benflumetol (1:6) compound fat emulsion below 25 ℃.
Three, the Artemether/benflumetol compound fat emulsified injection of different co-emulsifier preparations
Embodiment 5:
Prescription:
1200mg Artemether and 200mg benflumetol are put into the 8mL chloroform fully be dissolved into solution; this solution is mixed with 200g injection soybean oil; the antioxidant vitamin E that adds 12g soybean lecithin for injection, 0.15g behind the chloroform under nitrogen protection is removed in evaporation; in 60 ℃ of mixing, form oil mixture.900mL water for injection, 25g glycerol, 0.4g F68 in 60 ℃ of mixing, are formed aqueous mixture.Under nitrogen protection, aqueous mixture is mixed with oil mixture, add water to 1000mL, under 60 ℃, mechanical agitation 15min makes colostrum after the 8900r/min high speed dispersion, after regulating pH to 7.8, be to carry out homogenizing under the 110MPa condition 6 times at pressure, obtain uniform milky solution; Above-mentioned milky solution filters, logical nitrogen-sealed, and behind 125 ℃ of sterilization treatment 10min, storage is Artemether: benflumetol (6:1) compound fat emulsion below 25 ℃.
Embodiment 6:
Prescription:
100mg Artemether and 700mg benflumetol are put into the 8mL chloroform fully be dissolved into solution; this solution is mixed with 300g injection Oleum Camelliae; the antioxidant vitamin E that adds 24g injection Ovum Gallus domesticus Flavus lecithin, 0.21g behind the chloroform under nitrogen protection is removed in evaporation; in 70 ℃ of mixing, form oil mixture.900mL water for injection, 25g glycerol, 0.04g oleic acid in 70 ℃ of mixing, are formed aqueous mixture.Under nitrogen protection, aqueous mixture is mixed with oil mixture, add water to 1000mL, under 70 ℃, mechanical agitation 10min makes colostrum after the 9000r/min high speed dispersion, after regulating pH to 7.2, be to carry out homogenizing under the 108MPa condition 7 times at pressure, obtain uniform milky solution; Above-mentioned milky solution filters, logical nitrogen-sealed, and behind 120 ℃ of sterilization treatment 15min, storage is Artemether: benflumetol (1:7) compound fat emulsion below 25 ℃.
Four, the Artemether/benflumetol compound fat emulsified injection of different isoosmotic adjusting agent preparations
Embodiment 7:
Prescription:
200mg Artemether and 1200mg benflumetol are put into the 30mL isopropyl alcohol fully be dissolved into solution; this solution is mixed with 300g injection long chain triglycerides; the antioxidant vitamin E that adds 30g injection hydrogenated yolk lecithin, 0.23g behind the isopropyl alcohol under nitrogen protection is removed in evaporation; in 80 ℃ of mixing, form oil mixture.800mL water for injection, 25g glucose, 0.2g Tween 80 in 80 ℃ of mixing, are formed aqueous mixture.Under nitrogen protection, aqueous mixture is mixed with oil mixture, add water to 1000mL, under 80 ℃, mechanical agitation 5min makes colostrum after the 10000r/min high speed dispersion, after regulating pH to 7.8, be to carry out homogenizing under the 110MPa condition 6 times at pressure, obtain uniform milky solution; Above-mentioned milky solution filters, logical nitrogen-sealed, and behind 121 ℃ of sterilization treatment 15min, storage is Artemether: benflumetol (1:6) compound fat emulsion below 25 ℃.
Embodiment 8:
Prescription:
800mg Artemether and 200mg benflumetol are put into the 6mL chloroform fully be dissolved into solution; this solution is added and 150g injection Oleum Camelliae; the antioxidant vitamin E that adds 35g injection Ovum Gallus domesticus Flavus lecithin, 0.29g behind the chloroform under nitrogen protection is removed in evaporation; in 70 ℃ of mixing, form oil mixture.600mL water for injection, 25g glycerol, 0.6gF68 in 70 ℃ of mixing, are formed aqueous mixture.Under nitrogen protection, aqueous mixture is mixed with oil mixture, add water to 1000mL, under 70 ℃, mechanical agitation 10min makes colostrum after the 10000r/min high speed dispersion, after regulating pH to 7.4, be to carry out homogenizing under the 108MPa condition 7 times at pressure, obtain uniform milky solution; Above-mentioned milky solution filters, logical nitrogen-sealed, and behind 121 ℃ of sterilization treatment 15min, storage is Artemether: benflumetol (4:1) compound fat emulsion below 25 ℃.
Five, the animal experiment study of Artemether/benflumetol compound fat emulsion ejection preparation
5.1 the pharmacodynamic study of Artemether/benflumetol compound injection treatment malaria
5.1.1 animal
Kunming mouse, body weight 22 ± 1g, male and female half and half, Institute of Experimental Animals, Chinese Academy of Medical Sciences provides, the quality certification number: the SCXK(capital) 2004-0001; Bai Shi plasmodium worm strain (NK-173, Chinese microorganism of military medical sciences academy epidemic diseases provides).
5.1.2 method
The Peters method is adopted in test.Get Kunming mouse, by the body weight random packet, 10 of every treated animals, male and female half and half, be divided into model control group, positive controls: (concentration is respectively 0.8 to the artesunate sodium injection, 0.4,0.28,0.196,0.137,0.096mg/kg/d), Artemether among the embodiment/benflumetol compound fat emulsion administration group: Artemether: benflumetol 1:3(AL-LE-1), Artemether: benflumetol 3:1(AL-LE-2), Artemether: benflumetol 4:1(AL-LE-3), Artemether: benflumetol 1:5(AL-LE-4), Artemether: benflumetol 1:6(AL-LE-5), Artemether: benflumetol 6:1(AL-LE-6), Artemether: benflumetol 1:7(AL-LE-7) compound fat emulsion (concentration is respectively 0.8,0.4,0.28,0.196,0.137,0.096mg/kg/d), the tail vein injection administration.Model control group does not deal with.Respectively organize during experiment quantitatively to inoculate in the mouse peritoneal and contain l * 10
7Individual by the erythrocyte of Mus plasmodium parasitism, inoculum concentration 0.2ml/ only.Press the group administration in back second day in inoculation, press the 4d inhibition test method(s) of WHO regulation, successive administration 3 days.
After the administration 3 days, got blood from mousetail on the 4th day to be coated with the thin smear film sheet, with the dyeing of Giemsa staining, microscopically is observed, and counts 1 * 10
3Erythrocyte Central Plains borer population calculates erythrocytic infection rate (%).Examine under a microscope 50 oily mirror visuals field (* 1000, about 2.5 ten thousand erythrocyte), the person is decided to be negative blood sheet not observe the plasmodium, by formula one calculates each dosage group mice negative conversion rate (%).
Turn out cloudy as mice, then observe mice resume combustion situation in 30 days, be i.e. be coated with a thin smear film (inferior on every Wendesdays) next day, up to 30 days.Observe still that negative blood sheet person then is decided to be healing after 30 days, and two cure rates (%) that calculate each dosage group mice by formula.
5.1.3 result
The result sees Fig. 1, table 5.1 respectively.The microphotograph of blood was seen Fig. 2 after plasmodium and mice were turned out cloudy in the mouse blood.As can be seen from Figure 1: when administration concentration is 4mg/kg/day, behind the tail intravenously administrable 3 days, positive controls can be with the control of plasmodium infection rate below 35%, and AL-LE-1, AL-LE-4, AL-LE-5, AL-LE-7 can control the plasmodium infection rate below 25% simultaneously.But the plasmodium infection rate is still about 60% after 3 days for AL-LE-2, AL-LE-3 administration, and AL-LE-6 plasmodium infection rate is still about 42%.When administration concentration was 8mg/kg/day, AL-LE-5 and AL-LE-7 can be with the control of plasmodium infection rate below 3% after 3 days in administration, or even kill plasmodium fully.Simultaneously, AL-LE-4 also can be with the control of plasmodium infection rate in 15%.By contrast, 25% plasmodium infection rate is still arranged in the positive controls.This shows that the effect that the AL-LE-5 of this patent preparation and AL-LE-7 fat milk injection suppress growth of malaria parasites all is better than positive controls.
In addition, according to the data among Fig. 1, utilize SPSS11.5 can calculate each sample and suppress growth of malaria parasites 50% and 90% valid density, see Table 5.1.50% effective dose that this shows AL-LE-5 and AL-LE-7 inhibition growth of malaria parasites is about 1/2 of positive controls, proof Artemether/benflumetol compound fat emulsified injection has tangible killing action to plasmodium, and can effectively control plasmodial recurrence.
Table 5.1 positive controls, the plasmodial SD of AL-LE-1-7 couple P.berghei
50, SD
90Value.
5.2 Artemether of the present invention/benflumetol compound fat Emulsion is carried out safety testing
5.2.1 blood vessel irritation experiment:
Test method: every day is to rabbit injection 3.0ml/kg test sample (by the conversion of clinical application amount), after continuous three times, dissects animal blood vessels and makes the pathology sections observation, the reaction of significant stimulation such as inorganization degeneration or necrosis.
5.2.2 hemolytic experiment:
Method by new drug research safety testing guideline is carried out, and no haemolysis occurs.
5.2.3 systemic anaphylaxis experiment:
Method regulation by the Pharmacopoeia of the People's Republic of China is tested, result of the test: injecting the back the 14th day and 21 days first, phenomenons such as perpendicular hair, sneeze, retch, cough, dyspnea, rale, tic, collapse do not appear in animal in the 30min after Artemether/the benflumetol compound fat emulsion excites, show that Artemether/benflumetol compound fat emulsion Cavia porcellus systemic anaphylaxis result of the test is negative, this product does not have sensitization.
5.2.4 pyrogen test:
Test method: test with reference to 2005 editions appendix X of Chinese Pharmacopoeia III A pyrogen test, the result shows that Artemether/benflumetol compound fat emulsion is to rabbit blood vessel and the equal nonirritant of muscle, to the no anaphylaxis of Cavia porcellus test, rat there is not models of passive skin irritability, the compound pharmacopeia specified standard of no hemolytic and rabbit pyrogen test.Show that injection Artemether/benflumetol compound fat emulsion meets the requirement of safety indexes.
5.2.5 the stability test of Artemether/benflumetol compound fat emulsion
Get the fat milk of prepared fresh, place centrifuge tube, behind the centrifugal 15min of 13000rpm, do not find layering, do not see that also drug precipitation separates out.The shady and cool place of room temperature stores 1 year, and significant change does not all take place for physicochemical property such as Emulsion outward appearance, particle diameter, Zeta potential and content, shows that Emulsion is stable.
Claims (10)
1. Artemether/benflumetol compound fat emulsified injection, it is characterized in that component is: the Artemether of 0.01～1.5wt%, 0.01 the benflumetol of～3.5wt%, 10.0 the oil for injection of～30.0wt%, the emulsifying agent of 0.6～30wt%, the solubilizing agent of 0～10wt%, 0.01 the co-emulsifier of～5wt%, 2.25 the isotonic agent of～7wt%, the vitamin E of 0.002～0.075wt%, all the other are water for injection.
2. Artemether according to claim 1/benflumetol compound fat emulsified injection is characterized in that: described oil for injection be in soybean oil, Oleum Camelliae, Oleum Sesami, median chain triglyceride oil, long chain triglycerides or the olive oil any or appoint several.
3. Artemether according to claim 1/benflumetol compound fat emulsified injection, it is characterized in that: described emulsifying agent is Ovum Gallus domesticus Flavus lecithin, soybean lecithin, hydrogenated yolk lecithin, hydrogenated soy phosphatidyl choline or synthetic lecithin.
4. Artemether according to claim 1/benflumetol compound fat emulsified injection is characterized in that: described co-emulsifier be in Tween 80, F68 or the oleic acid any or appoint several.
5. Artemether according to claim 1/benflumetol compound fat emulsified injection, it is characterized in that: described solubilizing agent is dehydrated alcohol, chloroform or isopropyl alcohol.
6. Artemether according to claim 1/benflumetol compound fat emulsified injection, it is characterized in that: described isotonic agent is glycerol, glucose or xylitol.
7. according to the preparation method of described any Artemether of claim 1/benflumetol compound fat emulsion intravenous injection, comprise the steps:
A) solubilizing agent of the benflumetol of the Artemether of 0.01～1.5wt% and 0.01～3.5wt% being put into 0～10wt% is dissolved, and mixes with the oil for injection of 10.0～30.0wt% then, evaporates 10～60min and remove solubilizing agent in 40～80 ℃ of water-baths; Under nitrogen protection, add the emulsifying agent of 0.6～30wt% and the antioxidant of 0.002～0.075wt%, be heated to 40～80 ℃ and obtain forming oil mixture;
B) isotonic agent of 2.25～7wt%, co-emulsifier and the water for injection of 0.01～5wt% are mixed under 40～80 ℃, form aqueous mixture;
C) aqueous mixture that under nitrogen protection step 2 is obtained mixes with the oil mixture that step 1 obtains, then at 40～80 ℃, under 2000～18000r/min condition after the high speed dispersion, regulate pH to 6.0～9.0 with 0.1mol/L NaOH or HCL, be to carry out homogenizing under 70～110MPa condition 4～10 times at pressure, obtain uniform milky solution;
D) above-mentioned milky solution filtered, lead to nitrogen-sealed, behind 100～125 ℃ of sterilization treatment 10～30min, storage below 25 ℃.
8. the purposes of Artemether according to claim 1/benflumetol compound fat emulsified injection in the medicine of preparation treatment malaria.
9. purposes according to claim 8, this malaria are every other day, three days, pernicious, ovum type, brain type, gastrointestinal type, too high pattern of fever, blackwater fever, pernicious malaria and critical malaria.
10. Artemether according to claim 1/benflumetol compound fat emulsified injection, its route of administration is intravenous injection or intramuscular injection.
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| CN2013101698529A CN103251584A (en) | 2013-05-09 | 2013-05-09 | Preparation of artemether/benflumetol compound fat emulsion for injection and application of artemether/benflumetol compound fat emulsion in malaria treatment |
| PCT/CN2013/076463 WO2014180011A1 (en) | 2013-05-09 | 2013-05-30 | Preparation of artemether/benflumetol compound fat emulsion for injection, and application of same in malaria treatment |
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| CN2013101698529A CN103251584A (en) | 2013-05-09 | 2013-05-09 | Preparation of artemether/benflumetol compound fat emulsion for injection and application of artemether/benflumetol compound fat emulsion in malaria treatment |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2534623A (en) * | 2014-08-21 | 2016-08-03 | Simon Corbitt Terence | Formulations for transmucosal delivery |
| CN109663513A (en) * | 2018-05-10 | 2019-04-23 | 海南医学院 | A kind of preparation method and applications of Artemether lysate |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020225832A1 (en) * | 2019-05-07 | 2020-11-12 | Sveinbjorn Gizurarson | Preventing incompatibility among malarial drugs |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1065993A (en) * | 1990-08-08 | 1992-11-11 | 中国人民解放军军事医学科学院微生物流行病研究所 | The preparation method of synergistic antimalarial compound benzfluorenol |
| CN101032467A (en) * | 2007-04-13 | 2007-09-12 | 西安力邦制药有限公司 | Superregulated long-cycled lipid emulsion carrying medicine reagent for mainline |
| CN102895186A (en) * | 2012-09-13 | 2013-01-30 | 西安力邦制药有限公司 | Preparation of artesunate fat emulsion for injection and application of artesunate fat emulsion in treatment of malaria |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100463669C (en) * | 2006-08-31 | 2009-02-25 | 广州市医药工业研究所 | Self-emulsifying agent of compound artemether |
| CN102895187B (en) * | 2012-09-13 | 2015-05-06 | 西安力邦制药有限公司 | Preparation of benflumetol fat emulsion for injection and application of benflumetol fat emulsion in treatment of malaria |
-
2013
- 2013-05-09 CN CN2013101698529A patent/CN103251584A/en active Pending
- 2013-05-30 WO PCT/CN2013/076463 patent/WO2014180011A1/en active Application Filing
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1065993A (en) * | 1990-08-08 | 1992-11-11 | 中国人民解放军军事医学科学院微生物流行病研究所 | The preparation method of synergistic antimalarial compound benzfluorenol |
| CN101032467A (en) * | 2007-04-13 | 2007-09-12 | 西安力邦制药有限公司 | Superregulated long-cycled lipid emulsion carrying medicine reagent for mainline |
| CN102895186A (en) * | 2012-09-13 | 2013-01-30 | 西安力邦制药有限公司 | Preparation of artesunate fat emulsion for injection and application of artesunate fat emulsion in treatment of malaria |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2534623A (en) * | 2014-08-21 | 2016-08-03 | Simon Corbitt Terence | Formulations for transmucosal delivery |
| CN109663513A (en) * | 2018-05-10 | 2019-04-23 | 海南医学院 | A kind of preparation method and applications of Artemether lysate |
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| WO2014180011A1 (en) | 2014-11-13 |
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