CN1709252A - Preparations of artemisinin or its derivatives and amodiaquine or its derivatives and preparation method thereof - Google Patents
Preparations of artemisinin or its derivatives and amodiaquine or its derivatives and preparation method thereof Download PDFInfo
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- CN1709252A CN1709252A CN 200510026772 CN200510026772A CN1709252A CN 1709252 A CN1709252 A CN 1709252A CN 200510026772 CN200510026772 CN 200510026772 CN 200510026772 A CN200510026772 A CN 200510026772A CN 1709252 A CN1709252 A CN 1709252A
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Abstract
The present invention discloses a preparation made up by using artemisinin or its derivative and amodiaquine or its derivative and its preparation method. Said preparation is formed from active component and pharmaceutically-acceptable solid additive, the described active component is the mixture formed from artemisinin or its derivative and amodiaquine or its derivative. Said preparation can high-effectively and durably kill plasmodia.
Description
Technical field
The present invention relates to a kind of prevention and the arteannuin or derivatives thereof of treatment malaria and compound preparation of amodiaquine and preparation method thereof.
Background technology
Malaria is one of the most common disease in the torrid zone, subtropical zone.At present, nearly 100 the popular malaria of country in the whole world have people more than 2,500,000,000 to live in the malaria district occurred frequently, annual malaria morbidity number 3 to 500,000,000 people, and annual new 200～3,000,000 people that infect, the number that malaria is died from the whole world every year estimates at 100～3,000,000 people.Current more severe be that Plasmodium falciparum has been borrowed gene mutation or adaptive capacity that antimalarial commonly used has been produced drug resistance and spreads with high speed in each malaria district, the whole world, even more serious with south east asia.Though each state all prevents and treats the new antimalarial agent of Drug resistance worm strain in development, plasmodium is fast more than the speed of development new drug to the speed that new drug develops immunity to drugs, so that shortens greatly the service life of new drug.
The arteannuin or derivatives thereof, comprise the arteannuin and semi-synthetic derivant artesunate, Artemether, arteether and the dihydroarteannuin that come out from the Herba Artemisiae annuae separation and Extraction, being the new construction that same class contains peroxy-radical sesquiterpene ester, is the agent for killing of schizont (phorozoon) in the plasmodium.The malaria characteristics of this compounds are: 1. effective to anti-chloroquine pernicious malaria; 2. it is fast plasmodium erythrocytic stage phorozoon to be killed speed, and it is fast therefore to control the malaria symptom; 3. there is the effect of potentiation malaria to be worth (effect of tangible potentiation malaria being arranged) with amodiaquine 5 usefulness.Its shortcoming is that parasite killing is not thorough when the general treatment dosage and the short course of treatment (3 days), protozoon recrudescence rate height (reaching more than 50%), need escalated dose and extend the period of treatment (6～7 days) could thoroughly kill plasmodium and improve cure rate, but the often increase that causes drug toxicity owing to the increase and the prolongation of the course of treatment of dosage, wherein topmost is that neurotoxicity and is crossed reticulocyte minimizing symptom, therefore is greatly limited in clinical practice.
Amodiaquine and salt thereof belong to 4-quinolin-2-ylamine class antimalarial agent, and its structure is similar to the chloroquine that is all 4-quinolin-2-ylamine class with effect, and there are stronger killing action infrared phase and gametocyte, can effectively control malaria recurrence and propagation.The malaria characteristics of this compounds are: 1. effective to anti-chloroquine pernicious malaria; 2. various plasmodial phorozoons in the blood all there is stronger killing action, can controls clinical symptoms rapidly, gametocyte and the immature Plasmodium falciparum gametocyte of tertian malaria, ovale malaria and malariae also had killing action; 3. there is the effect of potentiation malaria to be worth (effect of tangible potentiation malaria being arranged) with other antimalarials, especially arteannuin and derivant (as artesunate) 5 usefulness thereof.Its shortcoming is that the toxicity of amodiaquine is bigger than other antimalarials, when every day, dosage surpassed 52.8mg, tired, dizzy, nauseating, vomiting, stomachache, cyanosis, medicine heat etc. easily take place, the minority erythrocyte lacks the patient of glucose 6-phosphate dehydrogenase, after the medication acute hemolytic anemia can take place, so WHO was once stoping once with its medicine as the treatment malaria.
At present, WHO recommends to adopt amodiaquine and artemisinin-based drug drug combination, still, because arteannuin or derivatives thereof and amodiaquine or derivatives thereof prepared respectively becomes tablet, therefore, the very easy mistake of taking medicine, especially be unwell to taking of old man and child, demand urgently improving.
Summary of the invention
The technical issues that need to address of the present invention are compound preparations that disclose a kind of arteannuin or derivatives thereof and amodiaquine or derivatives thereof and preparation method thereof, to overcome the above-mentioned shortcoming of arteannuin or derivatives thereof and amodiaquine drug combination.
The compound preparation of arteannuin or derivatives thereof of the present invention and amodiaquine is made up of active component and pharmaceutically acceptable solid additive.
Said active component is the mixture that arteannuin or derivatives thereof and amodiaquine or derivatives thereof are formed;
Said artemisinin derivative comprises arteannuin, dihydroarteannuin, Artemether, arteether, artesunate, sodium artesunate or the acid of Artemisia ether woods etc.;
Said amodiaquine derivant comprises the salt of amodiaquine or the free alkali of amodiaquine;
The salt of amodiaquine is selected from other salt of acceptable on the hydrochlorate of amodiaquine or the medicine, as sulfate, phosphate etc.Wherein:
The weight ratio of arteannuin or derivatives thereof and amodiaquine or derivatives thereof is:
Arteannuin or derivatives thereof: amodiaquine or derivatives thereof=1～10: 10～1, optimal proportion is 1～3: 3～1;
Said solid additive comprise filler or/and binding agent or/and solubilizing agent or/and disintegrating agent or/and fluidizer or/and antitack agent or/and lubricant or/and coloring agent;
Compound preparation of the present invention is an oral formulations, comprises tablet, capsule or granule;
Said tablet is selected from conventional tablet or coated tablet, as sugar-coat, gelatin clothing, casing, film-coat, double-contracting clothing or multiple coatings.
According to the preferred scheme of the present invention, in the compound preparation gross weight, constituent content is as follows:
Arteannuin or derivatives thereof 1～60%
Amodiaquine or amodiaquine derivant 5～90%
Filler 1～65%
Binding agent 1～20%
Solubilizing agent 0.1～5%
Disintegrating agent 1～50%
Fluidizer 0～10%
Antitack agent 0～10%
Lubricant 0～10%
Coloring agent 0.01～2%
Said filler is selected from one or more volumes of formulation that acquisition expectation can be provided or the chemical compound of weight, and preferred filler is selected from starch, dextrin, sucrose or lactose, cellulose or cellulosic derivant etc.;
Said binding agent is selected from one or more in polyvinylpyrrolidone, alginic acid, sodium alginate, hydroxypropyl emthylcellulose, the gelatin etc.;
Said solubilizing agent is selected from tween 80 or sodium lauryl sulphate etc.;
One or more chemical compounds of disintegrate when said disintegrating agent is selected from the preparation that can promote preparation of compositions and contacts with aqueous medium, preferred disintegrating agent is microcrystalline Cellulose, Powderd cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose or cross-linked carboxymethyl cellulose, carboxymethyl starch sodium etc.;
Said fluidizer is selected from one or more chemical compounds that can improve mobility of particle, as micropowder silica gel etc.
Said antitack agent can be to prevent that the tabletting raw material from adhering to one or more chemical compounds on drift or punch die surface, and preferred antitack agent is a Pulvis Talci etc.
Said lubricant is selected from fatty acid or derivative of fatty acid, for example calcium stearate, magnesium stearate etc.
Said coloring agent system is used to change the color of preparation, makes it that pleasing outward appearance be arranged, and one or more chemical compounds that patient or child are taken like a shot are preferably from amaranth, carmine, lemon yellow, indigo etc.
The preparation method of above-mentioned compound preparation comprises the steps:
Former, the adjuvant of recipe quantity is pulverized, is sieved, mix, with binding agent prepare granule, tablet, capsule or granule are made by preparation routine operation method in dry back;
Or various former, the adjuvant of recipe quantity pulverized, sieves, mix homogeneously prepares tablet or the direct fill capsule of powder prepares capsule by direct powder compression.
Animal experiment and clinical observation prove that the compound preparation of arteannuin or derivatives thereof of the present invention and amodiaquine or derivatives thereof has curative effect preferably.
The write out a prescription research of ratio of the present invention, be to consider that artemisinin derivatives has quick-acting efficient and amodiaquines and has and kill plasmodial advantage lastingly, avoid two kinds of medicines to use shortcoming (artemisinin derivatives recrudescence rate height, to use inconvenience, use toxic and side effects obvious in a large number in a short time separately simultaneously; The amodiaquine onset uses the toxic and side effects obvious slowly, in a large number), reduce the toxic and side effects used separately separately, improve onset speed, reduce recrudescence rate, improve the drug use comfort level, suitably reduce the medicine cost.The characteristics of forming new compound are low toxicity, efficient, convenient use, drug treatment weak point.The compound preparation of arteannuin or derivatives thereof of the present invention and amodiaquine or derivatives thereof, arteannuin or derivatives thereof and amodiaquine or derivatives thereof are mixed, simultaneously, various adjuvants have been added, compared with prior art, taking convenience is not easy the mistake of taking medicine, and especially is suitable for taking of old man and child.
The specific embodiment
Tablet in the embodiment 1 preparation compound preparation
1. write out a prescription
| Form | Weight | Effect | |
| ??I ? ? ? ? ? ??II ? ? ? ? ??III ? ? ? | Artesunate starch lactose dextrin lauryl sodium sulfate sodium carboxymethyl starch amodiaquine starch lactose dextrin sodium carboxymethyl starch sodium carboxymethyl starch hydroxypropyl cellulose microcrystalline cellulose dolomol | 50 grams, 20 grams, 12 grams, 4 grams, 4 grams, 10 grams, 150 grams, 50 grams, 30 grams, 10 grams, 10 grams, 10 grams, 10 grams, 20 grams, 10 grams | Active component filler filler filler solubilizer disintegrant active component filler filler filler disintegrant disintegrant disintegrant disintegrant lubricant |
| Gross weight | 400 grams |
2. preparation method
(1) former, the adjuvant of I part recipe quantity is crossed 80 mesh sieves after crushed after, mix homogeneously is crossed 40 mesh sieves, add 4% Gonak (binding agent) the system soft material that contains 1% tween 80 (solubilizing agent), cross 16 mesh sieves and granulate, in 50～60 ℃ of dryings, 16 mesh sieve granulate;
(2) former, the adjuvant of II part recipe quantity is crossed 80 mesh sieves after crushed after, mix homogeneously is crossed 40 mesh sieves, add 4% Gonak (binding agent) the system soft material that contains 1% tween 80 (solubilizing agent), cross 16 mesh sieves and granulate, in 50～60 ℃ of dryings, 16 mesh sieve granulate;
(3) above-mentioned two parts granule is mixed, add the adjuvant mix homogeneously of III part recipe quantity;
(4) tabletting, every heavily about 0.4 gram;
(5) with the gastric solubility acrylic resin routinely coating method carry out Cotton seeds, promptly get about 1000.
Tablet in the embodiment 2 preparation compound preparations
1. write out a prescription
| Form | Weight | Effect | |
| ????I | Artesunate starch lactose dextrin sodium lauryl sulphate carboxymethyl starch sodium | 100 grams, 25 grams, 16 grams, 8 grams, 6 grams, 15 grams | Active component filler filler filler solubilizing agent disintegrating agent |
| ????II ? ? ? ? ????III | Amodiaquine starch lactose dextrin sodium carboxymethyl starch sodium carboxymethyl starch hydroxypropyl cellulose microcrystalline cellulose dolomol | 300 grams, 60 grams, 35 grams, 10 grams, 15 grams, 13 grams, 13 grams, 22 grams, 12 grams | Active component filler filler filler disintegrant disintegrant disintegrant disintegrant lubricant |
| Gross weight | 650 grams |
2. preparation method
(1) former, the adjuvant of I part recipe quantity is crossed 80 mesh sieves after crushed after, mix homogeneously is crossed 40 mesh sieves, add 4% Gonak (binding agent) the system soft material that contains 1% tween 80 (solubilizing agent), cross 16 mesh sieves and granulate, in 50～60 ℃ of dryings, 16 mesh sieve granulate;
(2) former, the adjuvant of II part recipe quantity is crossed 80 mesh sieves after crushed after, mix homogeneously is crossed 40 mesh sieves, add 4% Gonak (binding agent) the system soft material that contains 1% tween 80 (solubilizing agent), cross 16 mesh sieves and granulate, in 50～60 ℃ of dryings, 16 mesh sieve granulate;
(3) above-mentioned two parts granule is mixed, add the adjuvant mix homogeneously of III part recipe quantity;
(4) tabletting, every heavily about 0.65 gram;
(5) with the gastric solubility acrylic resin routinely coating method carry out Cotton seeds, promptly get about 1000.
Tablet in the embodiment 3 preparation compound preparations
1. write out a prescription
| Form | Weight | Effect |
| Artesunate amodiaquine starch lactose dextrin lauryl sodium sulfate sodium carboxymethyl starch hydroxypropyl cellulose microcrystalline cellulose dolomol | 50 grams, 150 grams, 70 grams, 43 grams, 13 grams, 4 grams, 30 grams, 10 grams, 20 grams, 10 grams | Active component active component filler filler filler solubilizer disintegrant disintegrant disintegrant lubricant |
| Gross weight | 400 grams |
2. preparation method
(1) former, the adjuvant of above-mentioned recipe quantity is crossed 60 mesh sieves after crushed after, mix homogeneously is crossed 40 mesh sieves, adds magnesium stearate, mix homogeneously;
(2) direct powder compression method tabletting routinely, every heavily about 0.4 gram:
(3) with the gastric solubility acrylic resin routinely coating method carry out Cotton seeds, make 1000.
Tablet in the embodiment 4 preparation compound preparations
1. write out a prescription
| Form | Weight | Effect |
| Artesunate amodiaquine starch lactose dextrin lauryl sodium sulfate sodium carboxymethyl starch hydroxypropyl cellulose microcrystalline cellulose dolomol | 100 grams, 300 grams, 85 grams, 52 grams, 17 grams, 6 grams, 40 grams, 16 grams, 22 grams, 12 grams | Active component active component filler filler filler solubilizer disintegrant disintegrant disintegrant lubricant |
| Gross weight | 650 grams |
2. preparation method
(1) former, the adjuvant of above-mentioned recipe quantity is crossed 60 mesh sieves after crushed after, mix homogeneously is crossed 40 mesh sieves, adds magnesium stearate, mix homogeneously:
(2) direct powder compression method tabletting routinely, every heavy 0.65 gram;
(3) with the gastric solubility acrylic resin routinely coating method carry out Cotton seeds, make 1000.
Capsule in the embodiment 5 preparation compound preparations
1. write out a prescription
| Form | Weight | Effect | |
| ????I ? ? ? ? ? ? ????II ? ? ? ? ? ????III | Artesunate starch lactose dextrin lauryl sodium sulfate sodium carboxymethyl starch microcrystalline cellulose amodiaquine starch lactose dextrin sodium carboxymethyl starch microcrystalline cellulose talcum powder superfine silica gel powder dolomol | 50 grams, 10 grams, 5 grams, 1 gram, 3 grams, 10 grams, 6 grams, 150 grams, 25 grams, 15 grams, 4 grams, 10 grams, 7 grams, 8 grams, 1 gram, 5 grams | Active component filler filler filler solubilizer disintegrant disintegrant active component filler filler filler disintegrant disintegrant antitack agent glidant lubricant |
| Gross weight | 310 grams |
2. preparation method
(1) former, the adjuvant of I part recipe quantity is crossed 60 mesh sieves after crushed after, mix homogeneously is crossed 40 mesh sieves, to contain 5% polyvinylpyrrolidonesolution solution (binding agent) the system soft material of 1% tween 80 (solubilizing agent), cross 16 mesh sieves and granulate, in 50～60 ℃ of dryings, 16 mesh sieve granulate:
(2) former, the adjuvant of II part recipe quantity is crossed 60 mesh sieves after crushed after, mix homogeneously is crossed 40 mesh sieves, to contain 5% polyvinylpyrrolidonesolution solution (binding agent) the system soft material of 1% tween 80 (solubilizing agent), cross 16 mesh sieves and granulate, in 50～60 ℃ of dryings, 16 mesh sieve granulate;
(3) above-mentioned two parts granule is mixed, add the adjuvant mix homogeneously of III part recipe quantity;
(4) fill capsule, tolerant heavy about 0.31 gram of every intragranular.
Capsule in the embodiment 6 preparation compound preparations
1. write out a prescription
| Form | Weight | Effect | |
| ????I ? ? ? ? ? ? ????II ? ? ? ? ? ????III | Artesunate starch lactose dextrin lauryl sodium sulfate sodium carboxymethyl starch microcrystalline cellulose amodiaquine starch lactose dextrin sodium carboxymethyl starch microcrystalline cellulose talcum powder superfine silica gel powder dolomol | 100 grams, 13 grams, 6 grams, 2 grams, 5 grams, 11 grams, 8 grams, 300 grams, 35 grams, 20 grams, 6 grams, 16 grams, 10 grams, 10 grams, 2 grams, 6 grams | Active component filler filler filler solubilizer disintegrant disintegrant active component filler filler filler disintegrant disintegrant antitack agent glidant lubricant |
| Gross weight | 550 grams |
2. preparation method
(1) former, the adjuvant of I part recipe quantity is crossed 60 mesh sieves after crushed after, mix homogeneously is crossed 40 mesh sieves, adjoin pyrrolidone solution (binding agent) system soft material with 5% polyethylene that contains 1% tween 80 (solubilizing agent), cross 16 mesh sieves and granulate, in 50～60 ℃ of dryings, 16 mesh sieve granulate;
(2) former, the adjuvant of II part recipe quantity is crossed 60 mesh sieves after crushed after, mix homogeneously is crossed 40 mesh sieves, to contain 5% polyvinylpyrrolidonesolution solution (binding agent) the system soft material of 1% tween 80 (solubilizing agent), cross 16 mesh sieves and granulate, in 50～60 ℃ of dryings, 16 mesh sieve granulate;
(3) above-mentioned two parts granule is mixed, add the adjuvant mix homogeneously of III part recipe quantity;
(4) fill capsule, tolerant heavy about 0.55 gram of every intragranular.
Capsule in the embodiment 7 preparation compound preparations
1. write out a prescription
| Form | Weight | Effect |
| Artesunate amodiaquine starch lactose dextrin lauryl sodium sulfate sodium carboxymethyl starch microcrystalline cellulose talcum powder superfine silica gel powder dolomol | 50 grams, 150 grams, 35 grams, 20 grams, 4 grams, 3 grams, 20 grams, 14 grams, 8 grams, 1 gram, 5 grams | Active component active component filler filler filler solubilizer disintegrant disintegrant antitack agent glidant lubricant |
| Gross weight | 310 grams |
2. preparation method
(1) former, the adjuvant of above-mentioned recipe quantity is crossed 60 mesh sieves after crushed after, mix homogeneously is crossed 40 mesh sieves, adds Pulvis Talci, micropowder silica gel, magnesium stearate, mix homogeneously:
(2) fill capsule, tolerant heavy about 0.31 gram of every intragranular.
Capsule in the embodiment 8 preparation compound preparations
1. write out a prescription
| Form | Weight | Effect |
| Artesunate amodiaquine starch lactose dextrin lauryl sodium sulfate sodium carboxymethyl starch microcrystalline cellulose talcum powder superfine silica gel powder dolomol | 100 grams, 300 grams, 48 grams, 27 grams, 6 grams, 5 grams, 28 grams, 18 grams, 10 grams, 2 grams, 6 grams | Active component active component filler filler filler solubilizer disintegrant disintegrant antitack agent glidant lubricant |
| Gross weight | 550 grams |
2. preparation method
(1) former, the adjuvant of above-mentioned recipe quantity is crossed 60 mesh sieves after crushed after, mix homogeneously is crossed 40 mesh sieves, adds Pulvis Talci, micropowder silica gel, magnesium stearate, mix homogeneously;
(2) fill capsule, tolerant heavy about 0.55 gram of every intragranular.
Granule in the embodiment 9 preparation compound preparations
1. write out a prescription
| Form | Weight | Effect | |
| ??I ? ? ? ? ??II ? ? ? | Artesunate starch lauryl sodium sulfate sodium carboxymethyl starch microcrystalline cellulose amodiaquine starch sodium carboxymethyl starch microcrystalline cellulose | 50 grams, 190 grams, 10 grams, 30 grams, 40 grams, 150 grams, 400 grams, 55 grams, 75 grams | Active component filler solubilizer disintegrant disintegrant active component filler disintegrant disintegrant |
| Gross weight | 1000 grams |
2. preparation method
(1) former, the adjuvant of I part recipe quantity is crossed 80 mesh sieves after crushed after, mix homogeneously, cross 40 mesh sieves, to contain 5% polyvinylpyrrolidonesolution solution (binding agent) the system soft material of 1% tween 80 (solubilizing agent), 0.1% lemon yellow (coloring agent), crossing 16 mesh sieves granulates, in 50～60 ℃ of dryings, 16 mesh sieve granulate:
(2) former, the adjuvant of II part recipe quantity is crossed 80 mesh sieves after crushed after, mix homogeneously is crossed 40 mesh sieves, to contain 5% polyvinylpyrrolidonesolution solution (binding agent) the system soft material of 1% tween 80 (solubilizing agent), cross 16 mesh sieves and granulate, in 50～60 ℃ of dryings, 16 mesh sieve granulate;
(3) with above-mentioned two parts granule mix homogeneously;
(4) packing granule, about 1.0 grams of every bag.
Granule in the embodiment 10 preparation compound preparations
1. write out a prescription
| Form | Weight | Effect | |
| ????I ? ? ? ? ????II ? ? ? | Artesunate starch lauryl sodium sulfate sodium carboxymethyl starch microcrystalline cellulose amodiaquine starch sodium carboxymethyl starch microcrystalline cellulose | 100 grams, 150 grams, 10 grams, 25 grams, 35 grams, 300 grams, 270 grams, 45 grams, 65 grams | Active component filler solubilizer disintegrant disintegrant active component filler disintegrant disintegrant |
| Gross weight | 1000 grams |
2. preparation method
(1) former, the adjuvant of I part recipe quantity is crossed 80 mesh sieves after crushed after, mix homogeneously, cross 40 mesh sieves, to contain 5% polyvinylpyrrolidonesolution solution (binding agent) the system soft material of 1% tween 80 (solubilizing agent), 0.1% lemon yellow (coloring agent), crossing 16 mesh sieves granulates, in 50～60 ℃ of dryings, 16 mesh sieve granulate;
(2) former, the adjuvant of II part recipe quantity is crossed 80 mesh sieves after crushed after, mix homogeneously is crossed 40 mesh sieves, to contain 5% polyvinylpyrrolidonesolution solution (binding agent) the system soft material of 1% tween 80 (solubilizing agent), cross 16 mesh sieves and granulate, in 50～60 ℃ of dryings, 16 mesh sieve granulate;
(3) with above-mentioned two parts granule mix homogeneously;
(4) packing granule, about 1.0 grams of every bag.
Embodiment 11
1. artesunate and amodiaquine list are used the inhibiting observation of Mus malaria erythrocytic stage
Method: adopt four days inhibition methods, i.e. rbc is infected in mice do inoculation p.berghei ANKA strain, and every Mus is given first agent medicine after 5,000,000,4 hours, and successive administration 4 days is had a blood test, and asks the parasitemia negative conversion rate.The result is as follows:
Amodiaquine is to the inhibitory action of Mus malaria
| Dosage (mg/kg * 4) | Number of animals | The Mus number of turning out cloudy |
| ??1.29 ??1.62 ??2.03 ??2.62 ??ED 50??ED 95 | ??10 ??10 ??10 ??10 ??0.97(0.88～1.08) ??1.27(1.07～1.52) | ??0 ??2 ??8 ??10 |
Artesunate is to the inhibitory action of Mus malaria
| Dosage (mg/kg * 4) | Number of animals | The Mus number of turning out cloudy |
| ??0.64 ??0.86 ??1.15 ??1.54 ??1.81 ??ED 50??ED 95 | ??10 ??10 ??10 ??10 ??10 ??7.38(6.16～8.85) ??14.81(10.48～19.95) | ??0 ??1 ??3 ??6 ??7 |
2. artesunate and amodiaquine share Mus malaria erythrocytic stage inhibitory action
Experimental technique is the same.The ED of each medicine when asking artesunate and amodiaquine compatibility to use respectively
95, and make isoboles, the model of action of learning drug combination is addition.
3. artesunate and amodiaquine merge the experimental therapy of using infection Bai Shi plasmodium mice
Method: rbc, every Mus 5,000,000, d are infected in Kunming mouse do abdominal cavity inoculation p.berghei ANKA strain
3Treat that parasitemia reaches 5～10% back successive administrations 3 days, have a blood test, ask the parasitemia negative conversion rate.Adopt the preparation of embodiment 1 to carry out.The result is as follows:
| Medicine | Dosage (mg/kg * 3) | Number of animals | The Mus number of turning out cloudy |
| Amodiaquine | ??7.9 | ??10 | ??0 |
| ??9.0 ??11.5 ??14.5 ??18.0 ??ED 95?75.4(37.0～157.3) | ??10 ??10 ??10 ??10 | ??2 ??5 ??5 ??7 | |
| Artesunate | ??1.2 | ??10 | ??2 |
| ??1.5 ??1.9 ??2.3 ??2.9 ??ED 95?4.3(2.7～6.8) | ??10 ??10 ??10 ??10 | ??5 ??5 ??5 ??6 | |
| Artesunate and amodiaquine (1: 3) | ??10.8 | ??9 | ??0 |
| ??14.4 ??19.2 ??25.6 ??ED 95?30.1(22.5～40.3) | ??10 ??10 ??9 | ??1 ??6 ??7 |
The amalgamation mode of mixture is calculated by equation, and formula is as follows:
The expection ED of 1/ mixture
95The ED of=a/A chemical compound
95The ED of+b/BA chemical compound
95
(a, b is respectively A, B chemical compound shared ratio in mixture, a+b=1)
The above-mentioned formula of experimental result substitution is calculated expection ED
95=54.9.
According to Keplinger, ML etc., expection ED
95With actual measurement ED
95Ratio be antagonism less than 0.75,0.75～1.75 is summation action, greater than 1.75 for potentiation.
This experiment actual measurement ED
95Be 30.1, expection ED
95/ actual measurement ED
95=1.82 (＞1.75), so the drug combination model of action is judged to potentiation.
4. artesunate and amodiaquine share infecting the influence of Bai Shi plasmodium mice resume combustion at a specified future date
Artesunate merges to use with amodiaquine to be compared with independent application, no matter the plasmodium ANKA strain mice of infection medicine sensitivity or the Bai Shi plasmodium RL ANKA strain mice parasitemia of chloroquine resistance is turned out cloudy soon, and recrudescence rate at a specified future date is low.
Claims (11)
1. the preparation of arteannuin or derivatives thereof and amodiaquine or derivatives thereof is characterized in that, is made up of active component and pharmaceutically acceptable solid additive;
Said active component is the mixture that arteannuin or derivatives thereof and amodiaquine or derivatives thereof are formed.
2. preparation according to claim 1 is characterized in that, said artemisinin derivative comprises arteannuin, dihydroarteannuin, Artemether, arteether, artesunate, sodium artesunate or the acid of Artemisia ether woods; Said amodiaquine derivant comprises the salt of amodiaquine or the free alkali of amodiaquine.
3. preparation according to claim 2 is characterized in that, the salt of amodiaquine is selected from other salt of acceptable on the hydrochlorate of amodiaquine or the medicine.
4. preparation according to claim 1 is characterized in that: the weight ratio of arteannuin or derivatives thereof and amodiaquine or derivatives thereof is:
Arteannuin or derivatives thereof: amodiaquine or derivatives thereof=1～10: 10～1.
5. preparation according to claim 4 is characterized in that: the weight ratio of arteannuin or derivatives thereof and amodiaquine or derivatives thereof is: 1～3: 3～1.
6. preparation according to claim 1 is characterized in that: said solid additive comprise filler or/and binding agent or/and solubilizing agent or/and disintegrating agent or/and fluidizer or/and antitack agent or/and lubricant or/and coloring agent.
7. preparation according to claim 1 is characterized in that being oral formulations, comprises tablet, capsule or granule.
8. preparation according to claim 7 is characterized in that: said tablet is selected from conventional tablet or coated tablet.
9. preparation according to claim 1 is characterized in that: in the total formulation weight amount, constituent content is as follows:
Arteannuin or derivatives thereof 1～60%
Amodiaquine or amodiaquine derivant 5～90%
Filler 1～65%
Binding agent 1～20%
Solubilizing agent 0.1～5%
Disintegrating agent 1～50%
Fluidizer 0～10%
Antitack agent 0～10%
Lubricant 0～10%
Coloring agent 0.01～2%
10. according to each described preparation of claim 1～9, it is characterized in that: said filler is selected from one or more volumes of formulation that acquisition expectation can be provided or the chemical compound of weight, and preferred filler is selected from starch, dextrin, sucrose or lactose, cellulose or cellulosic derivant;
Said binding agent is selected from one or more in polyvinylpyrrolidone, alginic acid, sodium alginate, hydroxypropyl emthylcellulose, the gelatin;
Said solubilizing agent is selected from tween 80 or sodium lauryl sulphate etc.;
One or more chemical compounds of disintegrate when said disintegrating agent is selected from the preparation that can promote preparation of compositions and contacts with aqueous medium, preferred disintegrating agent is microcrystalline Cellulose, Powderd cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose or cross-linked carboxymethyl cellulose, carboxymethyl starch sodium etc.;
Said fluidizer is selected from one or more chemical compounds that can improve mobility of particle, as micropowder silica gel etc.
Said antitack agent can be to prevent that the tabletting raw material from adhering to one or more chemical compounds on drift or punch die surface, and preferred antitack agent is a Pulvis Talci etc.
Said lubricant is selected from fatty acid or derivative of fatty acid, for example calcium stearate, magnesium stearate etc.
Said coloring agent system is used to change the color of preparation, makes it that pleasing outward appearance be arranged, and one or more chemical compounds that patient or child are taken like a shot are preferably from amaranth, carmine, lemon yellow, indigo etc.
11. the preparation according to each described preparation of claim 1～10 is characterized in that: comprise the steps:
Former, the adjuvant of recipe quantity is pulverized, is sieved, mix, with binding agent prepare granule, tablet, capsule or granule are made by preparation routine operation method in dry back;
Or various former, the adjuvant of recipe quantity pulverized, sieves, mix homogeneously prepares tablet or the direct fill capsule of powder prepares capsule by direct powder compression.
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|---|---|---|---|
| CN 200510026772 CN1709252A (en) | 2005-06-15 | 2005-06-15 | Preparations of artemisinin or its derivatives and amodiaquine or its derivatives and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510026772 CN1709252A (en) | 2005-06-15 | 2005-06-15 | Preparations of artemisinin or its derivatives and amodiaquine or its derivatives and preparation method thereof |
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| CN1709252A true CN1709252A (en) | 2005-12-21 |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011032318A1 (en) * | 2009-09-21 | 2011-03-24 | 上海复星普适医药科技有限公司 | Stable artesunate-amodiaquine hydrochloride complex tablet and preparation method thereof |
| CN101011398B (en) * | 2006-12-26 | 2012-02-08 | 重庆医药工业研究院有限责任公司 | Amodiaquine hydrochloride coating particle and its preparation |
| CN101756982B (en) * | 2008-12-17 | 2012-07-04 | 重庆医药工业研究院有限责任公司 | Artesunate compound medicine composition with improved mouth feeling and high stability |
| CN101647799B (en) * | 2009-09-10 | 2013-07-10 | 上海星泰医药科技有限公司 | Stable artesunate amodiaquine hydrochloride compound tablet and preparation method thereof |
| CN111514300A (en) * | 2020-04-30 | 2020-08-11 | 中国中医科学院中药研究所 | An artemisinin enhanced pharmaceutical composition for preventing or treating malaria |
-
2005
- 2005-06-15 CN CN 200510026772 patent/CN1709252A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101011398B (en) * | 2006-12-26 | 2012-02-08 | 重庆医药工业研究院有限责任公司 | Amodiaquine hydrochloride coating particle and its preparation |
| CN101756982B (en) * | 2008-12-17 | 2012-07-04 | 重庆医药工业研究院有限责任公司 | Artesunate compound medicine composition with improved mouth feeling and high stability |
| CN101647799B (en) * | 2009-09-10 | 2013-07-10 | 上海星泰医药科技有限公司 | Stable artesunate amodiaquine hydrochloride compound tablet and preparation method thereof |
| WO2011032318A1 (en) * | 2009-09-21 | 2011-03-24 | 上海复星普适医药科技有限公司 | Stable artesunate-amodiaquine hydrochloride complex tablet and preparation method thereof |
| CN111514300A (en) * | 2020-04-30 | 2020-08-11 | 中国中医科学院中药研究所 | An artemisinin enhanced pharmaceutical composition for preventing or treating malaria |
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