CN100998569A - Compound antimalarial three-layered tablets containing artemisinin or its derivatives and its preparing method - Google Patents
Compound antimalarial three-layered tablets containing artemisinin or its derivatives and its preparing method Download PDFInfo
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Abstract
A three-layer compound antimalarial tablet containing artemisinin or its derivative is composed of an artemisinin or its derivative layer, another antimalarial medicine layer and an isolating layer. Its preparing process is also disclosed.
Description
Technical field
The present invention relates to field of medicaments, relate in particular to antimalarial medicine and preparation method thereof.
Background technology
Malaria has another name called " malaria ", is by the infectious disease of plasmodium through propagating by mosquito bite.Bring down a fever with shiver with cold, hyperpyrexia, the perspiration of periodicity timing property outbreak clinically and sings and symptomses such as anemia and splenomegaly are characteristics.Because of differences such as protozoon strain, gradient of infection, immune state and reactivities of organism, clinical symptoms and the performance of outbreak rule differ.Malaria outbreak can be divided into for three phases: during cold stage, patient has violent shiver with cold, and xerosis cutis can have cyanosis, during body temperature progressively rise, this phase is continuously 15 minutes to 1 hour; During pyrogenic stage, after shiver with cold stopped, patient had hyperpyrexia, xerosis cutis, and flushed face, pulse is loud strong, and blood pressure gradually falls, and accelerated breathing, body temperature can rise to 40 ℃ or higher, have a headache after socket of the eye is often arranged, and be thirsty and vomiting, dysphoria etc. are often arranged; To sweating stage, the patient perspires in a large number, the whole body dripping sweat, and patient symptom is alleviated, and body temperature descends, even can be lower than normally, and extremely tired sense is arranged this moment.But the new cases of infection symptom of subtertian malaria and tertian malaria often is not true to type, and mistaken diagnosis is flu easily.
Subtertian malaria is the most dangerous a kind of malaria, and fatal complication can take place, and sings and symptoms often lacks feature, and the encephalopathy of the various causes of disease in similar other diseases, particularly flu, viral hepatitis and the coma patient.Subtertian malaria incubation period is 8～15 days, and precursor symptom Chang Yanchong: patient feels depression, discomfort, severe headache, muscle particularly waist and sacroiliac pain, and shiver with cold and nausea,vomiting,diarrhea are also common.
On March 10th, 2005, famous Britain " nature " magazine has been delivered a research report.Report is pointed out: the whole world has 500,000,000 people of surpassing to be infected with malaria every year.And malariated high-risk group's quantity reaches 2,200,000,000, and this numeral has surpassed 1/3rd of world population.And that influenced maximum is the child.The life that malaria is seized every year will surpass the acquired immune deficiency syndrome (AIDS) that is considered to the No.1 infectious disease in the world, and it is human No.1 killer.Africa has 1,000,000 children below 5 years old to die from malaria now every year.Report thinks that the menace of malaria is significantly underestimated, and it has become the maximum killer of developing country's health of people.There were 5.15 hundred million malaria infection persons in the whole world in 2002, was the twice that World Health Organization (WHO) announced numeral in 1998.According to the report of WHO, about 2,500,000,000 people in the whole world live in the malaria district, and annual clinical case number reaches 3～500,000,000 people, and year dead population surpasses nearly 3,000,000 people.
For a long time, antimalarial agent is mainly based on quinine class medicine.Since the sixties, chloroquine produced resistance, a lot of countries were all at the research new antimalarial agent, ten thousand kinds of chemical compounds surplus the U.S. has screened 30, with mefloquine for well, as focus development.But this medicine easily produces resistance, and bad independent use once was used with sulfamethoxine, pyrimethamine, make oral DAT " Fansimef ", but the discovered in recent years mefloquine had neurotoxicity.
Early seventies, Chinese scholar are isolated the antimalarial arteannuin in Chinese herbal medicine Hemerocallis citrina Baroni Artemisia after, again successively partial synthesis effective derivants such as Artemether, artesunate and dihydroarteannuin.Along with the diffusion of multi-drug resistance plasmodium strain, arteannuin medicine has become effective line medicine of treatment resistance subtertian malaria at present.But this class drug half-life is short, and recrudescence rate is high slightly, and the cost height also might bring out the generation drug resistance.There is the recrudescence rate of report arteannuin very high, do not use clinically in fact substantially.Also there is similar problem in artemisinin derivative.There are some results of study to show that on Hainan, Yunnan and other places, in vitro tests shows that some plasmodiums have been downward trend to arteannuin and derivant sensitivity thereof recently.
The severe problem that malaria prophylaxis and therapeutic purposes face at present is a drug resistance, Plasmodium falciparum has produced drug resistance to most of antimalarial, and the drug resistance of antimalarial causes the infected's number to increase severely and bring more serious, more complicated malaria, the encephalic malaria very high as mortality rate ...The current pernicious malaria that accounts for world's malaria morbidity sum 80% is to developed immunity to drugs worm strain and all spread with high speed in each epidemic-stricken area, the whole world of antimalarial commonly used.Press for for this reason and create new antimalarial agent.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.In the epidemic-stricken area, most of patients is annual wants repeatedly ill, and the antimalarial agent of life-time service heavy dose can cause more and more significant toxic and side effects.On the other hand, the popular regional resident living level of most of malaria is lower, is difficult to pay expensive treatment cost and is used for buying the artemisinin-based antimalarial drug thing, has only the medicine of reduction purchase cost could fundamentally solve the malaria treatment problem.In view of this, must adopt two or more that research channel of the medication combined application of potentiation value is arranged for the research of new antimalarial agent.
This phenomenon has caused the attention of World Health Organization (WHO), and what WHO proposed is that use is united with conventional medicament in the basis with the artemisinin-based drug, is to tackle the chemical sproof effective way of pernicious malaria.WHO in 2006 requires drugmaker to terminate listing and sells antimalarial artemisine single preparations of ephedrine, and purpose is to emphasize to use the artemisine drug combination, to prevent malarial parasite such medicine is developed immunity to drugs.
Artemisinin-based drug can reduce the multi-drug resistant plasmodium rapidly, and the nubbin plasmodium just can be killed by the combination medicine of high concentration, and the medication combined use of different mechanism of action has improved curative effect.Simultaneously, because curative effect of medication is high and the minimizing of gametocyte quantity, can weaken malaria transmission, and plasmodium is also lower to two kinds of all drug-fast probabilities of medicine, the plasmodium drug resistance should be quite slow due to the drug combination.Therefore artemisinin-based drug and other antimalarials unite use treat malaria can be very effective.
At present, the packing method of the drug combination of selling on the market is that two kinds of different medicinal tablets are pressed on the same bubble cap tray, needs when patient takes two kinds of different pharmaceuticals are taken out, and quantitatively takes.Adopt this kind packing method the situation that patient misses a certain medicine usually to occur, the compliance of patient can't be protected, thereby has influence on the protection of the antagonism property of medicine.If can prepare the compound preparation of two kinds of medicines that comprise fixed dosage, just can fundamentally address the above problem.Therefore, this area presses for steady quality, compound preparation that bioavailability is good.
Summary of the invention
One of purpose of the present invention provides a kind of steady quality, good arteannuin or derivatives thereof and other antimalarials (antimalarial except that the arteannuin or derivatives thereof) compound preparation of bioavailability, overcomes the deficiencies in the prior art.
Another object of the present invention provides the preparation method of above-mentioned compound preparation.
Design of the present invention is such:
Since the arteannuin or derivatives thereof with can cause arteannuin or derivatives thereof stability decreases after other antimalarials mix, therefore, compound preparation of the present invention is provided with sealing coat between two-layer active ingredient, with influencing each other of two kinds of compositions in the solution compound preparation, improve stability; On the other hand, two kinds of active ingredients have good dissolution simultaneously, could guarantee the bioavailability of each composition, the present invention solves compound preparation bioavailability problem by the adjuvant and the proportioning of preferred arteannuin or derivatives thereof layer, other antimalarial agent layers and sealing coat.
A first aspect of the present invention discloses a kind of compound antimalarial preparation, is made up of a kind of arteannuin or derivatives thereof, one or more other antimalarial agents and acceptable adjuvant medically;
Wherein the arteannuin or derivatives thereof is selected from a kind of in arteannuin, dihydroarteannuin, Artemether, arteether, artesunate, sodium artesunate, the acid of Artemisia ether woods etc.;
Other antimalarials are meant the antimalarial except that the arteannuin or derivatives thereof, are selected from quinine and analog thereof, chloroquine and analog thereof, primaquine and analog thereof, pyrimethamine and the analog thereof etc. one or more;
Medically acceptable adjuvant comprises filler and/or coloring agent and/or solubilizing agent and/or binding agent and/or disintegrating agent and/or lubricant and coating material, coating material.
The said compound antimalarial preparation of the present invention, be made up of artesunate, one or more other antimalarials and acceptable adjuvant medically, other antimalarials are selected from one or more in quinine and analog, chloroquine and analog thereof, primaquine and analog thereof, pyrimethamine and the analog thereof etc.;
The said compound antimalarial preparation of the present invention, by Artemether, benflumetol and medically the acceptable adjuvant form.
Product of the present invention is an oral administered dosage form, and preferred dosage form is a three-layer tablet.
Contain a three-tier system in the product of the present invention, comprise arteannuin or derivatives thereof layer, other antimalarial layer and sealing coats of compound recipe with it, wherein:
Contain the active ingredient that accounts for this layer granule gross weight 1～30% in the prescription of ground floor arteannuin or derivatives thereof layer, 0.1～1% coating material or coating material (whether taking or specifically take which kind of technology to decide) on medicine, 1～70% filler, 0～2% solubilizing agent, 0～20% binding agent, 1～50% disintegrating agent and 0.5～2% lubricant;
Contain the filler that accounts for this layer granule gross weight 1～95% in the prescription of second layer sealing coat, the coating material of 1～20% binding agent and 0.5～2% lubricant and 0.1～1%;
Contain the active ingredient that accounts for this layer granule gross weight 10～80% in the prescription of the 3rd layer of other antimalarial layer, 0.1～1% coating material or coating material (whether taking or specifically take which kind of technology to decide) on medicine, 1～40% filler, 0～2% solubilizing agent, 0～20% binding agent, 1～30% disintegrating agent and 0.5～2% lubricant.
Said coating material is selected from one or more in gelatin, polyvinylpyrrolidone, hypromellose, carmethose, hyprolose, methylcellulose, the ethyl cellulose etc.
Said coating material is selected from one or more in polyvinylpyrrolidone, hypromellose, ethyl cellulose, acrylic resin IV number, methylcellulose, acrylic resin II number, phthalic acid acetate etc.
Said solubilizing agent is anion surfactant and/or non-ionic surface active agent, preferably from polyoxyethylene sorbitan monoleate and/or sodium lauryl sulphate etc.
The said compound antimalarial three-layered tablets of the present invention, each layer adjuvant all is selected from:
Filler is one or more the combination in starch, amylum pregelatinisatum, dextrin, sucrose or the lactose etc.; Binding agent is one or more the combination in gelatinized corn starch, Icing Sugar gelatinized corn starch, polyvinylpyrrolidonesolution solution, hypromellose solution or the ethanol etc.; Disintegrating agent is one or more the combination in microcrystalline Cellulose, carboxymethylstach sodium, hyprolose, cross-linked carboxymethyl cellulose sodium or the crospolyvinylpyrrolidone etc.; Lubricant is magnesium stearate and/or Pulvis Talci.
Compound antimalarial three-layered tablets disclosed by the invention, wherein sealing coat can comprise coloring agent, is selected from carmine, amaranth, lemon yellow, indigo, eosin, methylene blue, cocoa powder, Brilliant blue aluminum lake, light green aluminum color lake etc. one or more.
A second aspect of the present invention discloses compound antimalarial three-layered tablets preparation technology, comprises the steps:
(1) granulates
Ground floor arteannuin or derivatives thereof layer granule is to be made by (or coating) again after active ingredient (or after packing encystation) and filler, solubilizing agent, binding agent, disintegrating agent, the mix lubricant;
Second layer sealing coat granule be by after filler, coloring agent, binding agent, the mix lubricant again coating make;
The 3rd layer of other antimalarial layer granule is to be made by (or coating) again after active ingredient (or after packing encystation) and filler, solubilizing agent, binding agent, disintegrating agent, the mix lubricant;
(2) tabletting
Comprise sheeting process three times, wherein twice is prepressing procedures: promptly fill earlier ground floor arteannuin or derivatives thereof layer granule, the precompressed ground floor is packed into the sealing coat granule precompressed second layer again after to be formed, after the molding, be packed into another kind of antimalarial layer granule at last and be pressed into three-layer tablet.
The said compound antimalarial three-layered tablets preparation technology who comprises artesunate of the present invention comprises the steps:
(1) granulates
Ground floor artesunate layer granule, active ingredient packs into earlier microcapsule, makes again with after filler, solubilizing agent, binding agent, disintegrating agent, the mix lubricant;
Second layer sealing coat granule be by after filler, coloring agent, binding agent, the mix lubricant again coating make;
The 3rd layer of other antimalarial layer granule is by making after active ingredient and filler, solubilizing agent, binding agent, disintegrating agent, the mix lubricant;
(2) tabletting
Comprise sheeting process three times, wherein twice is prepressing procedures: promptly fill earlier ground floor artesunate layer granule, the precompressed ground floor is packed into the sealing coat granule precompressed second layer again after to be formed, after the molding, be packed into another kind of antimalarial layer granule at last and be pressed into three-layer tablet.
The said compound antimalarial three-layered tablets preparation technology who is made up of Artemether, benflumetol of the present invention comprises the steps: preparation technology, comprises the steps:
(1) granulates
Ground floor Artemether layer granule makes after active ingredient and filler, solubilizing agent, binding agent, disintegrating agent, the mix lubricant;
Second layer sealing coat granule be by after filler, coloring agent, binding agent, the mix lubricant again coating make;
The 3rd layer of benflumetol layer granule, after active ingredient and filler, binding agent, disintegrating agent, the mix lubricant again coating make;
(2) tabletting
Comprise sheeting process three times, wherein twice is prepressing procedures: promptly fill earlier ground floor Artemether layer granule, the precompressed ground floor is packed into the sealing coat granule precompressed second layer again after to be formed, after the molding, is packed into benflumetol layer granule at last and is pressed into three-layer tablet.
Compound antimalarial three-layered tablets disclosed by the invention has following advantage:
(1) in the three-layer tablet sealing coat is set,, avoids direct contact from physically separating arteannuin or derivatives thereof and other antimalarials; The sealing coat granule is carried out coating, can stop effectively further that the different activities composition moves at interlayer; On the other hand, the selected coating material of the present invention has good cohesive, makes sealing coat and arteannuin or derivatives thereof layer and other antimalarial layers well to bond, and can not cause sliver because of sealing coat makes moist.
(2) on technology, active ingredient is carried out microencapsulation and handle, make the encapsulated material parcel of active ingredient, prevent that on the one hand the active ingredient contact causes the tablet quality instability in the tabletting process; On the other hand, microencapsulation has improved by the dissolution of bag medicine.
(3) because three-layer tablet of the present invention is selected to have used the microencapsulation technology, selected suitable disintegrating agent and solubilizing agent combination, the dissolution of active ingredient is all reached more than 80%, bioavailability is good.
Compound antimalarial three-layered tablets disclosed by the invention, taking convenience, patient dependence is good, the situation of a certain medicine can not occur missing, and is especially for old man and child, significant.
The specific embodiment
The said filler of the present invention 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 one or more in starch, amylum pregelatinisatum, dextrin, sucrose or the lactose.
The said binding agent of the present invention is selected from one or more in gelatinized corn starch, Icing Sugar gelatinized corn starch, polyvinylpyrrolidonesolution solution, hypromellose solution or the ethanol.
One or more chemical compounds of disintegrate when the said disintegrating agent of the present invention is selected from the preparation that can promote preparation of compositions and contacts with aqueous medium, preferred disintegrating agent are one or more in microcrystalline Cellulose, carboxymethylstach sodium, hyprolose, cross-linked carboxymethyl cellulose sodium or the crospolyvinylpyrrolidone etc.
Hyprolose, microcrystalline Cellulose are cellulose derivative, the hygroscopicity preferably and the water absorption of tool, this character has increased its swelling capacity greatly, the fineness of dispersion after can quickening the disintegrate of tablet and improving disintegrate, thereby accelerate the dissolution rate of medicine, improve bioavailability.
Carboxymethylstach sodium is the potato starch derivant, and it is moist that tool stronger drawn, and water absorbing force is big, can absorb 30 times of its dry bulk.Suction back powder expands and does not dissolve, so do not hinder the continuation infiltration of moisture content and influence the further disintegrate of slice, thin piece, is a good disintegrating agent, can accelerate the dissolution rate of medicine, improves bioavailability.
The said solubilizing agent of the present invention is anion surfactant and/or non-ionic surface active agent, preferably from polyoxyethylene sorbitan monoleate and/or sodium lauryl sulphate etc.
The solubilizing agent polyoxyethylene sorbitan monoleate that the present invention uses is a nonionic surfactant, and sodium lauryl sulphate is an anion surfactant.Tablet is with after gastric juice contacts, and solubilizing agent can reduce its surface tension, increases the wettability of slice, thin piece, makes moisture content borrow the capillarity of tablet, and rapid permeability causes disintegrate to label.But its independent action effect is not good enough, share with disintegrating agent of the present invention, can play auxiliary disintegrate and use.
The said lubricant of the present invention is selected from and can improves mobility of particle, and can prevent that the tabletting raw material from adhering to one or more chemical compounds on drift or punch die surface, and preferred lubricant is magnesium stearate and/or Pulvis Talci.
The said coloring agent of the present invention system is used to change the color of preparation, make it that pleasing outward appearance be arranged, one or more chemical compounds that patient or child are taken like a shot, water solublity or water-insoluble two classes are arranged, preferred one or more in carmine, amaranth, lemon yellow, indigo, eosin, methylene blue, cocoa powder, Brilliant blue aluminum lake, light green aluminum color lake etc., the optimal coloring agent is a carmine.
The said coating material of the present invention is selected from one or more in polyvinylpyrrolidone, hypromellose, ethyl cellulose, acrylic resin IV number, methylcellulose, acrylic resin II number, phthalic acid acetate etc., is preferably ethyl cellulose.
The said coating material of the present invention is selected from one or more in gelatin, polyvinylpyrrolidone, hypromellose, carmethose, hyprolose, methylcellulose, the ethyl cellulose etc., is preferably hypromellose.
Tablet forming technique
Among the said compound antimalarial three-layered tablets preparation technology of the present invention sheeting process is arranged three times, wherein twice is prepressing procedures: promptly fill ground floor arteannuin or derivatives thereof layer granule earlier, the precompressed ground floor, be packed into the sealing coat granule precompressed second layer again after to be formed, after the molding, be packed into another kind of antimalarial layer granule at last and be pressed into three-layer tablet.
Preparation technology of the present invention, should consider following factor:
The medicated layer granule should have certain adhesive property and be beneficial to the tablet molding, good flowability also will be arranged to guarantee the accurate of filling dose, should be able to guarantee also that at last the dissolution of medicine can meet the requirement of quality standard;
The sealing coat granule at first would not exert an influence to two kinds of stability of drug, only be to isolate the particulate effect of all the other two parts, secondly should have good adhesive property, can become a slice with other two parts granule secure bond, and the sliver situation can not appear, also good flowability should be arranged at last.
Sealing coat is provided with
Having added the sealing coat technology among the said preparation technology of the present invention, is for causing quality unstable specially designed after avoiding the arteannuin or derivatives thereof and other antimalarials directly contacting.Sealing coat mainly plays buffer action, the sealing coat granule does not contain any active ingredient, can the stability of arteannuin or derivatives thereof or other antimalarials not being exerted an influence, only is that arteannuin or derivatives thereof and other antimalarial two parts granules are kept apart, and avoids its direct contact.
The sealing coat granule is carried out coating stopped that effectively a kind of antimalarial moves to another kind of antimalarial layer by sealing coat, and because selected coating material has good cohesive, make sealing coat and medicated layer can well be bonded to a slice, can not cause sliver because of sealing coat makes moist.
Coating or encapsulation
Among the said preparation technology of the present invention to a kind of microencapsulation or the Cotton seeds of having carried out in two kinds of antimalarials of compound recipe.Carrying out that microencapsulation handles is in order to prevent that in the tabletting process sheet from contact two kinds of antimalarials that cause compound recipe indirectly and directly contacting and cause the tablet quality instability and the measure taked with sheet; Carrying out Cotton seeds is at environment is relatively more responsive to external world individually, the protective measure that the unsettled antimalarial of quality is taked.Specifically take which kind of protective measure to decide on medicine.
Coating or encapsulation can be according to a conventional method, and with ethyl cellulose among the embodiment 3 artesunate being carried out encapsulation is example, and preparation method is as follows:
Ethyl cellulose is dissolved in CH
2Cl
2, artesunate disperses in 30 ℃ of water, mixes with ethyl cellulose solution, stirs to be added to down to form O/W type emulsion in 30 ℃ of water that contain 0.5% polysorbate60, water temperature is risen to 40 ℃ gradually, continues to stir 3 hours, and filtration, washing, drying at room temperature are promptly.
Its product of the said compound antimalarial three-layered tablets of the present invention is mainly used in the treatment of pernicious malaria, mainly puts on the patient who needs treatment by oral mode.
Below in conjunction with embodiment, the present invention is described further, but the present invention is not limited to following embodiment.
Among the embodiment, if no special instructions, constituent content all is weight percentage.
Embodiment 1
1. malanidine layer granule write out a prescription
Prescription is formed the consumption purposes
Malanidine 100mg active ingredient
Starch 16% filler
Sucrose 10% filler
Dextrin 5% filler
Polyoxyethylene sorbitan monoleate 0.1% solubilizing agent
Hypromellose solution 4% binding agent
Hyprolose 4% disintegrating agent
Microcrystalline Cellulose 10% disintegrating agent
Carboxymethylstach sodium 6% disintegrating agent
Magnesium stearate 1% lubricant
More than being with the particulate weight of this layer is benchmark, down together.
2. the sealing coat granule is write out a prescription
Prescription is formed the consumption purposes
I starch 68.3% filler
Sucrose 18% filler
Dextrin 6% filler
Amaranth 0.1 ‰ coloring agent
Gelatinized corn starch 6% binding agent
Magnesium stearate 1% lubricant
II hypromellose 0.6% coating material
Macrogol 4000 0.1% coating material
3. artesunate layer granule write out a prescription
Prescription is formed the consumption purposes
I artesunate 50mg active ingredient
Hypromellose 0.5% coating material
Polyoxyethylene sorbitan monoleate 0.2% coating material
II starch 28% filler
Sucrose 15% filler
Dextrin 8% filler
Hyprolose 5% disintegrating agent
Microcrystalline Cellulose 15% disintegrating agent
Carboxymethylstach sodium 6% disintegrating agent
Magnesium stearate 0.5% lubricant
4. preparation method
(1) the particulate preparation of malanidine layer
Take by weighing malanidine by the prescription consumption, pulverizing is crossed 60 mesh sieves.Take by weighing starch, sucrose, dextrin, hyprolose, microcrystalline Cellulose, carboxymethylstach sodium and magnesium stearate by the prescription consumption, cross 60 mesh sieves respectively.With malanidine and starch, sucrose, dextrin mix homogeneously, add the hypromellose solution that contains polyoxyethylene sorbitan monoleate, granulate, oven dry, granulate is again with hyprolose, microcrystalline Cellulose, carboxymethylstach sodium and magnesium stearate mix homogeneously;
(2) the particulate preparation of sealing coat
Take by weighing starch, sucrose, dextrin by the prescription consumption, cross mix homogeneously behind 60 mesh sieves respectively, add the gelatinized corn starch that contains amaranth, granulate, oven dry, granulate, coating is again with the magnesium stearate mix homogeneously;
(3) the particulate preparation of artesunate layer
Take by weighing artesunate by the prescription consumption, pulverizing is crossed 100 mesh sieves, packs into microcapsule.Take by weighing starch, sucrose, dextrin, carboxymethylstach sodium, microcrystalline Cellulose, hyprolose and magnesium stearate by the prescription consumption, cross behind 60 mesh sieves respectively and artesunate microcapsule mix homogeneously;
(4) preparation of artesunate malanidine three-layer tablet
Malanidine layer granule, sealing coat granule and artesunate layer granule are packed into tablet machine successively, and tabletting can make artesunate malanidine three-layer tablet.
Adopt HPLC method and ultraviolet spectrophotometry to carry out the finished product chemical examination, the result:
Content (%) dissolution (%)
Artesunate 98.8 89.6
Malanidine 97.9 74.2
The result of accelerated test is as follows:
Keep sample the time (moon) 01236
Related substance is up to specification up to specification
Content artesunate 99.5 99.3 99.3 99.1 98.9
(%) malanidine 99.8 99.8 99.5 99.4 99.0
Conclusion: 6th month stability data of three-layer tablet is still up to specification.
Embodiment 2
1. NAPHTHOQUINE PHOSPHATE layer granule write out a prescription
Prescription is formed the consumption purposes
NAPHTHOQUINE PHOSPHATE 200mg active ingredient
Starch 7% filler
Dextrin 6% filler
Sodium lauryl sulphate 1% solubilizing agent
Hypromellose solution 4% binding agent
Hyprolose 3% disintegrating agent
Microcrystalline Cellulose 3% disintegrating agent
Carboxymethylstach sodium 3% disintegrating agent
Magnesium stearate 1% lubricant
2. the sealing coat granule is write out a prescription
Prescription is formed the consumption purposes
I starch 40% filler
Sucrose 28% filler
Dextrin 25% filler
Indigo 0.1 ‰ coloring agent
Gelatinized corn starch 5% binding agent
Magnesium stearate 1% lubricant
II ethyl cellulose 0.9% coating material
Macrogol 4000 0.1% coating material
3. artesunate layer granule write out a prescription
Prescription is formed the consumption purposes
I artesunate 50mg active ingredient
Methylcellulose 0.5% coating material
II starch 22% filler
Sucrose 13% filler
Dextrin 5% filler
Hyprolose 2% disintegrating agent
Microcrystalline Cellulose 8% disintegrating agent
Carboxymethylstach sodium 7% disintegrating agent
Magnesium stearate 1% lubricant
4. preparation method
(1) the particulate preparation of NAPHTHOQUINE PHOSPHATE layer
Take by weighing NAPHTHOQUINE PHOSPHATE by the prescription consumption, pulverizing is crossed 60 mesh sieves.Take by weighing starch, dextrin, hyprolose, microcrystalline Cellulose, carboxymethylstach sodium and magnesium stearate by the prescription consumption, cross 60 mesh sieves respectively.With NAPHTHOQUINE PHOSPHATE and starch, dextrin mix homogeneously, add the hypromellose solution that contains sodium lauryl sulphate, granulate, oven dry, granulate is again with hyprolose, microcrystalline Cellulose, carboxymethylstach sodium and magnesium stearate mix homogeneously;
(2) the particulate preparation of sealing coat
Take by weighing starch, sucrose, dextrin by the prescription consumption, cross mix homogeneously behind 60 mesh sieves respectively, add and contain indigo gelatinized corn starch, granulate, oven dry, granulate, coating is again with the magnesium stearate mix homogeneously;
(3) the particulate preparation of artesunate layer
Take by weighing artesunate by the prescription consumption, pulverizing is crossed 100 mesh sieves, packs into microcapsule.Take by weighing starch, sucrose, dextrin, hyprolose, microcrystalline Cellulose, carboxymethylstach sodium and magnesium stearate by the prescription consumption, cross behind 60 mesh sieves respectively and artesunate microcapsule mix homogeneously;
(4) preparation of artesunate NAPHTHOQUINE PHOSPHATE three-layer tablet
NAPHTHOQUINE PHOSPHATE layer granule, sealing coat granule and artesunate layer granule are packed into tablet agent successively, and tabletting can make artesunate NAPHTHOQUINE PHOSPHATE three-layer tablet.
Adopt HPLC method and ultraviolet spectrophotometry to carry out the finished product chemical examination, the result:
Content (%) dissolution (%)
Artesunate 99.1 88.8
NAPHTHOQUINE PHOSPHATE 98.9 78.2
The result of accelerated test is as follows:
Keep sample the time (moon) 01236
Related substance is up to specification up to specification
Content artesunate 99.9 99.8 99.5 99.3 99.0
(%) NAPHTHOQUINE PHOSPHATE 99.5 99.3 99.1 98.8 98.7
Conclusion: 6th month stability data of three-layer tablet is still up to specification.
Embodiment 3
1. the piperaquine phosphate granule is write out a prescription
Prescription is formed the consumption purposes
Piperaquine phosphate 250mg active ingredient
Starch 10% filler
Sucrose 7% filler
Dextrin 4% filler
Polyoxyethylene sorbitan monoleate 0.2% solubilizing agent
Gelatinized corn starch 5% binding agent
Hyprolose 4% disintegrating agent
Microcrystalline Cellulose 7% disintegrating agent
Carboxymethylstach sodium 6% disintegrating agent
Magnesium stearate 0.5% lubricant
2. the sealing coat granule is write out a prescription
Prescription is formed the consumption purposes
I starch 49.3% filler
Sucrose 26% filler
Dextrin 18% filler
Carmine 0.1 ‰ coloring agent
Gelatinized corn starch 5% binding agent
Magnesium stearate 1% lubricant
II acrylic resin IV number 0.6% coating material
Oleum Ricini 0.1% coating material
3. artesunate layer granule write out a prescription
Prescription is formed the consumption purposes
I artesunate 50mg active ingredient
Ethyl cellulose 0.5% coating material
II starch 30% filler
Sucrose 25% filler
Dextrin 11% filler
Gelatinized corn starch 6% binding agent
Hyprolose 4% disintegrating agent
Microcrystalline Cellulose 10% disintegrating agent
Carboxymethylstach sodium 5% disintegrating agent
Magnesium stearate 1% lubricant
4. preparation method
(1) the particulate preparation of piperaquine phosphate layer
Take by weighing piperaquine phosphate by the prescription consumption, pulverizing is crossed 60 mesh sieves.Take by weighing starch, sucrose, dextrin, hyprolose, microcrystalline Cellulose, carboxymethylstach sodium and magnesium stearate by the prescription consumption, cross 60 mesh sieves respectively.With piperaquine phosphate and starch, sucrose, dextrin mix homogeneously, add the gelatinized corn starch that contains polyoxyethylene sorbitan monoleate, granulate, oven dry, granulate is again with hyprolose, microcrystalline Cellulose, carboxymethylstach sodium and magnesium stearate mix homogeneously;
(2) the particulate preparation of sealing coat
Take by weighing starch, sucrose, dextrin by the prescription consumption, cross mix homogeneously behind 60 mesh sieves respectively, add the gelatinized corn starch that contains carmine, granulate, oven dry, granulate, coating is again with the magnesium stearate mix homogeneously;
(3) the particulate preparation of artesunate layer
Take by weighing artesunate by the prescription consumption, pulverizing is crossed 100 mesh sieves, packs into microcapsule.Take by weighing after starch, sucrose, dextrin cross 60 mesh sieves respectively and mix by the prescription consumption, add gelatinized corn starch, granulate, oven dry, granulate mixes with hyprolose, microcrystalline Cellulose, carboxymethylstach sodium and magnesium stearate, again with artesunate microcapsule mix homogeneously;
(4) preparation of artesunate piperaquine phosphate three-layer tablet
Piperaquine phosphate layer granule, sealing coat granule and artesunate layer granule are packed into tablet agent successively, and tabletting can make artesunate piperaquine phosphate three-layer tablet.
Adopt HPLC method and ultraviolet spectrophotometry to carry out the finished product chemical examination, the result:
Content (%) dissolution (%)
Artesunate 98.8 85.7
Piperaquine phosphate 98.1 80.3
The result of accelerated test is as follows:
Keep sample the time (moon) 01236
Related substance is up to specification up to specification
Content artesunate 99.7 99.7 99.5 99.2 98.8
(%) piperaquine phosphate 99.9 99.6 99.5 99.0 98.6
Conclusion: 6th month stability data of three-layer tablet is still up to specification.
Embodiment 4
1. Fansidar layer granule write out a prescription
Prescription is formed the consumption purposes
Sulfadoxine 500mg active ingredient
Pyrimethamine 25mg active ingredient
Starch 7% filler
Sodium lauryl sulphate 2% solubilizing agent
Ethanol 2% binding agent
Hyprolose 4% disintegrating agent
Carboxymethylstach sodium 5% disintegrating agent
Magnesium stearate 1% lubricant
2. the sealing coat granule is write out a prescription
Prescription is formed the consumption purposes
I starch 40% filler
Sucrose 13% filler
Dextrin 40% filler
Carmine 0.1 ‰ coloring agent
Icing Sugar gelatinized corn starch 5% binding agent
Magnesium stearate 1% lubricant
II hypromellose 0.8% coating material
Macrogol 4000 0.1% coating material
Polyoxyethylene sorbitan monoleate 0.1% coating material
3. artesunate layer granule write out a prescription
Prescription is formed the consumption purposes
I artesunate 50mg active ingredient
Hypromellose 0.8% coating material
II starch 21% filler
Sucrose 13% filler
Gelatinized corn starch 4% binding agent
Hyprolose 18% disintegrating agent
Microcrystalline Cellulose 20% disintegrating agent
Carboxymethylstach sodium 9% disintegrating agent
Magnesium stearate 1% lubricant
4. preparation method
(1) the particulate preparation of Fansidar layer
Take by weighing sulfadoxine and pyrimethamine by the prescription consumption, pulverizing is crossed 60 mesh sieves.Take by weighing starch, sodium lauryl sulphate, hyprolose, carboxymethylstach sodium and magnesium stearate by the prescription consumption, cross 60 mesh sieves respectively.With sulfadoxine and pyrimethamine and starch, sodium lauryl sulphate mix homogeneously, add 75% ethanol, granulate, oven dry, granulate is again with hyprolose, carboxymethylstach sodium and magnesium stearate mix homogeneously;
(2) the particulate preparation of sealing coat
Take by weighing starch, sucrose, dextrin by the prescription consumption, cross mix homogeneously behind 60 mesh sieves respectively, add the Icing Sugar gelatinized corn starch that contains carmine, granulate, oven dry, granulate, coating is again with the magnesium stearate mix homogeneously;
(3) the particulate preparation of artesunate layer
Take by weighing artesunate by the prescription consumption, pulverizing is crossed 100 mesh sieves, packs into microcapsule.Take by weighing after starch, sucrose crosses 60 mesh sieves respectively and mix by the prescription consumption, add gelatinized corn starch, granulate, oven dry, granulate mixes with hyprolose, microcrystalline Cellulose, carboxymethylstach sodium and magnesium stearate, again with artesunate microcapsule mix homogeneously;
(4) preparation of artesunate Fansidar three-layer tablet
Fansidar layer granule, sealing coat granule and artesunate layer granule are packed into tablet agent successively, and tabletting can make artesunate Fansidar three-layer tablet.
Adopt the HPLC method to carry out the finished product chemical examination, the result:
Content (%) dissolution (%)
Artesunate 99.6 89.4
Sulfadoxine 99.1 84.9
Pyrimethamine 98.6 85.6
The result of accelerated test is as follows:
| Keep sample the time (moon) | 0 | 1 | 2 | 3 | 6 | |
| Related substance | Up to specification | Up to specification | Up to specification | Up to specification | Up to specification | |
| Content (%) | The artesunate Fansidar | 100.0 99.4 98.8 | 99.9 99.1 98.4 | 99.4 98.5 98.0 | 99.1 98.2 97.6 | 98.9 98.0 97.4 |
Conclusion: 6th month stability data of three-layer tablet is still up to specification.
Embodiment 5
1. Artemether layer granule write out a prescription
Prescription is formed the consumption purposes
Artemether 20mg active ingredient
Starch 30% filler
Lactose 15% filler
Polyoxyethylene sorbitan monoleate 1.5% solubilizing agent
Gelatinized corn starch 4% binding agent
Magnesium stearate 1% lubricant
2. the sealing coat granule is write out a prescription
Prescription is formed the consumption purposes
I starch 66.2% filler
Sucrose 25% filler
Carmine 0.1 ‰ coloring agent
Icing Sugar gelatinized corn starch 7% binding agent
Magnesium stearate 1% lubricant
II ethyl cellulose 0.8% coating material
3. benflumetol layer granule write out a prescription
Prescription is formed the consumption purposes
I benflumetol 50mg active ingredient
Starch 19% filler
Sucrose 9% filler
Gelatinized corn starch 3% binding agent
Microcrystalline Cellulose 22% disintegrating agent
Carboxymethylstach sodium 7% disintegrating agent
Magnesium stearate 1% lubricant
II hypromellose 0.7% coating material
Macrogol 4000 0.3% coating material
4. preparation method
(1) the particulate preparation of Artemether layer
Take by weighing Artemether by the prescription consumption, pulverizing is crossed 60 mesh sieves.Take by weighing starch, lactose and magnesium stearate by the prescription consumption, cross 60 mesh sieves respectively.With Artemether and starch, lactose mix homogeneously, add the gelatinized corn starch that contains polyoxyethylene sorbitan monoleate, granulate, oven dry, granulate is again with the magnesium stearate mix homogeneously;
(2) the particulate preparation of sealing coat
Take by weighing starch, sucrose by the prescription consumption, cross mix homogeneously behind 60 mesh sieves respectively, add the Icing Sugar gelatinized corn starch that contains carmine, granulate, oven dry, granulate, coating is again with the magnesium stearate mix homogeneously;
(3) the particulate preparation of benflumetol layer
Take by weighing benflumetol by the prescription consumption, pulverizing is crossed 60 mesh sieves, takes by weighing starch, sucrose by the prescription consumption and crosses 60 mesh sieves respectively, benflumetol is mixed the back add gelatinized corn starch with starch, sucrose, granulate, oven dry, granulate is behind the coating, with carboxymethylstach sodium, microcrystalline Cellulose, magnesium stearate mix homogeneously;
(4) preparation of Artemether benflumetol three-layer tablet
Artemether layer granule, sealing coat granule and benflumetol layer granule are packed into tablet agent successively, and tabletting can make Artemether benflumetol three-layer tablet.
Adopt ultraviolet spectrophotometry and HPLC method to carry out the finished product chemical examination, the result:
Content (%) dissolution (%)
Artemether 99.0 93.2
Benflumetol 98.7 84.3
The result of accelerated test is as follows:
| Keep sample the time (moon) | 0 | 1 | 2 | 3 | 6 | |
| Related substance | Up to specification | Up to specification | Up to specification | Up to specification | Up to specification | |
| Content (%) | The Artemether benflumetol | 99.3 98.8 | 99.5 98.6 | 98.7 98.1 | 98.4 97.9 | 97.9 97.7 |
Conclusion: 6th month stability data of three-layer tablet is still up to specification.
Claims (14)
1. antimalarial-compound preparation is made up of a kind of arteannuin or derivatives thereof, one or more other antimalarial agents and acceptable adjuvant medically;
Wherein the arteannuin or derivatives thereof is selected from a kind of in arteannuin, dihydroarteannuin, Artemether, arteether, artesunate, sodium artesunate, the acid of Artemisia ether woods etc.;
Other antimalarials are meant the antimalarial except that the arteannuin or derivatives thereof, are selected from quinine and analog thereof, chloroquine and analog thereof, primaquine and analog thereof, pyrimethamine and the analog thereof etc. one or more;
Medically acceptable adjuvant comprises filler and/or coloring agent and/or solubilizing agent and/or binding agent and/or disintegrating agent and/or lubricant and coating material, coating material.
2. according to the compound preparation of claim 1, it is characterized in that said preparation is a three-layer tablet, comprise arteannuin or derivatives thereof layer, other antimalarial layer and sealing coats of compound recipe with it, wherein:
Ground floor arteannuin or derivatives thereof layer is made up of active ingredient arteannuin or derivatives thereof and adjuvant, and second layer sealing coat does not contain any pharmaceutical compositions, is made up of adjuvant merely, and the 3rd layer of other antimalarial layer are made up of other antimalarials of active ingredient and adjuvant.
3. antimalarial-compound preparation according to claim 2, it is characterized in that, contain the active ingredient that accounts for this layer granule gross weight 1～30% in the prescription of ground floor arteannuin or derivatives thereof layer, 0.1～1% coating material or coating material, 1～70% filler, 0～2% solubilizing agent, 0～20% binding agent, 1～50% disintegrating agent and 0.5～2% lubricant;
Contain the filler that accounts for this layer granule gross weight 1～95% in the prescription of second layer sealing coat, be no more than 0.1 ‰ coloring agent, the coating material of 1～20% binding agent and 0.5～2% lubricant and 0.1～1%;
Contain the active ingredient that accounts for this layer granule gross weight 10～80% in the prescription of the 3rd layer of other antimalarial layer, 0.1～1% coating material or coating material, 1～40% filler, 0～2% solubilizing agent, 0～20% binding agent, 1～30% disintegrating agent and 0.5～2% lubricant.
4. antimalarial-compound preparation according to claim 2, it is characterized in that said coating material is selected from one or more in gelatin, polyvinylpyrrolidone, hypromellose, carmethose, hyprolose, methylcellulose, the ethyl cellulose etc.
5. antimalarial-compound preparation according to claim 2, it is characterized in that said coating material is selected from one or more in polyvinylpyrrolidone, hypromellose, ethyl cellulose, acrylic resin IV number, methylcellulose, acrylic resin II number, phthalic acid acetate etc.
6. antimalarial-compound preparation according to claim 2 is characterized in that, said solubilizing agent is anion surfactant and/or non-ionic surface active agent, preferably from polyoxyethylene sorbitan monoleate and/or sodium lauryl sulphate etc.
7. according to each described antimalarial-compound preparation of claim 1～6, it is characterized in that filler is selected from one or more in starch, amylum pregelatinisatum, dextrin, sucrose or the lactose etc.;
Binding agent is selected from one or more in gelatinized corn starch, Icing Sugar gelatinized corn starch, polyvinylpyrrolidonesolution solution, hypromellose solution or the ethanol etc.;
Disintegrating agent is selected from one or more in microcrystalline Cellulose, carboxymethylstach sodium, hyprolose, cross-linked carboxymethyl cellulose sodium or the crospolyvinylpyrrolidone etc.;
Lubricant is magnesium stearate and/or Pulvis Talci.
8. antimalarial-compound preparation according to claim 7, it is characterized in that, sealing coat can comprise coloring agent, is selected from carmine, amaranth, lemon yellow, indigo, eosin, methylene blue, cocoa powder, Brilliant blue aluminum lake, light green aluminum color lake etc. one or more.
9. compound preparation according to claim 1, it is characterized in that, wherein said arteannuin or derivatives thereof is an artesunate, and other antimalarials are selected from one or more in quinine and analog, chloroquine and analog thereof, primaquine and analog thereof, pyrimethamine and the analog thereof etc.
10. compound preparation according to claim 1 is characterized in that, wherein said arteannuin or derivatives thereof is an Artemether, and other antimalarials are benflumetol.
11. antimalarial-compound preparation according to claim 2 is characterized in that, comprises the steps:
(1) granulates
Ground floor arteannuin or derivatives thereof layer granule is to be made by (or coating) again after active ingredient (or after packing encystation) and filler, solubilizing agent, binding agent, disintegrating agent, the mix lubricant;
Second layer sealing coat granule be by after filler, coloring agent, binding agent, the mix lubricant again coating make;
The 3rd layer of other antimalarial layer granule is to be made by (or coating) again after active ingredient (or after packing encystation) and filler, solubilizing agent, binding agent, disintegrating agent, the mix lubricant;
(2) tabletting
Comprise sheeting process three times, wherein twice is prepressing procedures: promptly fill earlier ground floor arteannuin or derivatives thereof layer granule, the precompressed ground floor is packed into the sealing coat granule precompressed second layer again after to be formed, after the molding, be packed into another kind of antimalarial layer granule at last and be pressed into three-layer tablet.
12. antimalarial-compound preparation according to claim 9 is characterized in that, comprises the steps:
(1) granulates
Ground floor artesunate layer granule, active ingredient packs into earlier microcapsule, makes again with after filler, solubilizing agent, binding agent, disintegrating agent, the mix lubricant;
Second layer sealing coat granule be by after filler, coloring agent, binding agent, the mix lubricant again coating make;
The 3rd layer of other antimalarial layer granule is by making after active ingredient and filler, solubilizing agent, binding agent, disintegrating agent, the mix lubricant;
(2) tabletting
Comprise sheeting process three times, wherein twice is prepressing procedures: promptly fill earlier ground floor artesunate layer granule, the precompressed ground floor is packed into the sealing coat granule precompressed second layer again after to be formed, after the molding, be packed into another kind of antimalarial layer granule at last and be pressed into three-layer tablet.
13. antimalarial-compound preparation according to claim 10 is characterized in that, comprises the steps:
(1) granulates
Ground floor Artemether layer granule makes after active ingredient and filler, solubilizing agent, binding agent, disintegrating agent, the mix lubricant;
Second layer sealing coat granule be by after filler, coloring agent, binding agent, the mix lubricant again coating make;
The 3rd layer of benflumetol layer granule, be by after active ingredient and filler, binding agent, disintegrating agent, the mix lubricant again coating make;
(2) tabletting
Comprise sheeting process three times, wherein twice is prepressing procedures: promptly fill earlier ground floor Artemether layer granule, the precompressed ground floor is packed into the sealing coat granule precompressed second layer again after to be formed, after the molding, is packed into benflumetol layer granule at last and is pressed into three-layer tablet.
14., it is characterized in that wherein said granulation step adopts wet granulation and/or dry granulation according to each described compound antimalarial three-layered tablets of claim 11～13.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2006101488304A CN100998569A (en) | 2006-12-30 | 2006-12-30 | Compound antimalarial three-layered tablets containing artemisinin or its derivatives and its preparing method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2006101488304A CN100998569A (en) | 2006-12-30 | 2006-12-30 | Compound antimalarial three-layered tablets containing artemisinin or its derivatives and its preparing method |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN100998569A true CN100998569A (en) | 2007-07-18 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2006101488304A Pending CN100998569A (en) | 2006-12-30 | 2006-12-30 | Compound antimalarial three-layered tablets containing artemisinin or its derivatives and its preparing method |
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| Country | Link |
|---|---|
| CN (1) | CN100998569A (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101984970A (en) * | 2010-11-23 | 2011-03-16 | 浙江华立南湖制药有限公司 | Dihydroartemisinin piperaquine phosphate tablets and preparation process thereof |
| CN102283829A (en) * | 2011-06-24 | 2011-12-21 | 成都恩威投资（集团）有限公司 | Anti-malarial medicinal composition and preparation method and application thereof |
| CN102688239A (en) * | 2011-03-24 | 2012-09-26 | 昆明制药集团股份有限公司 | Compound naphthoquine phosphate pellets and preparation method thereof |
| CN105380912A (en) * | 2014-09-03 | 2016-03-09 | 长春海悦药业有限公司 | Tadalafil-containing pharmaceutical composition |
| CN110604733A (en) * | 2019-09-19 | 2019-12-24 | 同济大学 | Application of artemisinin drugs in preparation of antimalarial drugs by combining with other drugs |
-
2006
- 2006-12-30 CN CNA2006101488304A patent/CN100998569A/en active Pending
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101984970A (en) * | 2010-11-23 | 2011-03-16 | 浙江华立南湖制药有限公司 | Dihydroartemisinin piperaquine phosphate tablets and preparation process thereof |
| CN102688239A (en) * | 2011-03-24 | 2012-09-26 | 昆明制药集团股份有限公司 | Compound naphthoquine phosphate pellets and preparation method thereof |
| CN102688239B (en) * | 2011-03-24 | 2014-02-05 | 昆明制药集团股份有限公司 | Compound naphthoquine phosphate pellets and preparation method thereof |
| CN102283829A (en) * | 2011-06-24 | 2011-12-21 | 成都恩威投资（集团）有限公司 | Anti-malarial medicinal composition and preparation method and application thereof |
| CN102283829B (en) * | 2011-06-24 | 2013-09-25 | 成都恩威投资（集团）有限公司 | Anti-malarial medicinal composition and preparation method and application thereof |
| CN105380912A (en) * | 2014-09-03 | 2016-03-09 | 长春海悦药业有限公司 | Tadalafil-containing pharmaceutical composition |
| CN105380912B (en) * | 2014-09-03 | 2018-09-11 | 长春海悦药业股份有限公司 | A kind of pharmaceutical composition containing Tadalafei |
| CN110604733A (en) * | 2019-09-19 | 2019-12-24 | 同济大学 | Application of artemisinin drugs in preparation of antimalarial drugs by combining with other drugs |
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Open date: 20070718 |