CN101623270A - Stable artesunate and amodiaquine hydrochloride bilayer tablet and preparation method thereof - Google Patents
Stable artesunate and amodiaquine hydrochloride bilayer tablet and preparation method thereof Download PDFInfo
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- CN101623270A CN101623270A CN200810204298A CN200810204298A CN101623270A CN 101623270 A CN101623270 A CN 101623270A CN 200810204298 A CN200810204298 A CN 200810204298A CN 200810204298 A CN200810204298 A CN 200810204298A CN 101623270 A CN101623270 A CN 101623270A
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Abstract
The invention provides an artesunate and amodiaquine hydrochloride bilayer tablet and a preparation method thereof. In the invention, isopropanol is adopted in the process of wet granulating, thus avoiding water contact in the process and controlling hydrolysis to lighten the catalytic effect of acid or alkali on esterolysis; in addition, calcium carbonate is added in the preparation process, thus avoiding the effect of the hydrochloric acid contained in the amodiaquine hydrochloride and improving the stability of the preparation. In the artesunate and amodiaquine hydrochloride bilayer tablet of the invention, the dissolution rate of the artesunate achieves over 75% and that of the amodiaquine achieves over 80% within 30min, which are far beyond the dissolution rate of the artesunate in the Chinese Pharmacopeia, namely 60%, and the dissolution rate of the amodiaquine in the United States Pharmacopeia, namely 75%.
Description
Technical field
The present invention relates to pharmaceutical preparation, be specifically related to a kind of stable artesunate and amodiaquine hydrochloride bilayer tablet and preparation method thereof.
Background technology
Artesunate mainly acts on the wireless body of plasmodium erythrocytic stage, and model of action mainly is to disturb pellicle one mitochondrial function, and it has following effect characteristics: 1) effective to anti-chloroquine pernicious malaria; 2) can kill plasmodium erythrocytic stage phorozoon fast, control malaria symptom; 3) compare with other antimalarials, this product side effect is little.But this product half-life is short, short course of therapy, and parasite killing is not thorough, protozoon recrudescence rate height, need extend the period of treatment (6-7 days) could thoroughly be killed plasmodium and improve cure rate.And it is compared with other antimalarials, and price comparison is expensive, and clinical practice is subjected to certain limitation.
The amodiaquine structure is similar with chloroquine to effect, can effectively kill various cruel protozoon phorozoons in the erythrocytic stage, and the ripe gametocyte of tertian malaria, quartan malaria and ovale malaria is also had certain effect, but then invalid to the infrared phase plasmodium of the paulospore in the hepatocyte.It has following effect characteristics: 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, the ripe gametocyte and the immature Plasmodium falciparum gametocyte of tertian malaria, quartan malaria and ovale malaria also had killing action; 3) cheap, determined curative effect and toleration are good when being used for the treatment of malaria, thus in African area will its as a line malaria medicine for treatment.But this product toxicity is bigger than other antimalarials.
Artesunate and amodiaquine compound preparation are the most effective anti-malaria medicaments at present, and cure rate of its treatment malaria can reach 95%, and onset time is shorter than single preparations of ephedrine.Can significantly improve the malaria curative effect, limit drug-fast propagation.WHO recommends drug combination (ACT) based on arteannuin as a line malaria medication, and it is generally believed is the preferred plan for the treatment of subtertian malaria.Be used for the treatment of various malaria, especially treat other antimalarial (as chloroquine) is produced the malaria that drug-fast Plasmodium falciparum causes, also be used for the acute attack of malaria, have good tolerability.Artesunate and amodiaquine are prepared into compound preparation, reduce the mistake that occurs in the drug combination process thing phenomenon (especially at the child) of taking medicine, on the basis that does not change the original pharmaceutically active of medicine, be convenient to people's taking convenience, reduce dosage simultaneously, reduce side effect.
In existing artesunate and the amodiaquine compound preparation preparation process, artesunate all is easy to hydrolysis under acidity or alkali condition, following reaction takes place:
The unstability that has caused compound preparation.
Summary of the invention:
Technical problem to be solved by this invention is to overcome above-mentioned weak point, improves the prescription and the preparation method of artesunate and amodiaquine compound preparation, strengthens stability of formulation
The invention provides a kind of artesunate and amodiaquine hydrochloride bilayer tablet, form by following raw materials in weight portion:
Artesunate layer: artesunate: 100 parts
Calcium carbonate: 45-55 part
Pregelatinized Starch: 15-45 part
Microcrystalline Cellulose: 40-75 part
Polyvidone: 2.5-5.5 part
Cross-linking sodium carboxymethyl cellulose: 20-30 part
Magnesium stearate: 2.7 parts
Silicon dioxide: 0.8-1 part;
Amodiaquine layer: Camoquin: 352-353 part
Microcrystalline Cellulose: 40-80 part
Polyvidone: 0-30 part
Magnesium stearate: 3-8 part
Silicon dioxide: 3-5 part.
Another object of the present invention has provided the preparation method of a kind of artesunate and amodiaquine hydrochloride bilayer tablet.
Double-layer tablet of the present invention adopts the wet granulation that replaces water with isopropyl alcohol respectively with artesunate layer and amodiaquine layer, fills then and is pressed into double-layer tablet.This double-layer tablet has guaranteed the curative effect of medicine on the basis of the stability that has guaranteed each layer active constituents of medicine.
The inventive method comprises the following steps:
(1) artesunate layer preparation of granules: with wet granulation behind artesunate, calcium carbonate, pregelatinized Starch, polyvidone, cross-linking sodium carboxymethyl cellulose and the silicon dioxide mix homogeneously, sieve at 30 ℃-40 ℃ dry back 1.4mm, add cross-linking sodium carboxymethyl cellulose, microcrystalline Cellulose and 2.7 parts of magnesium stearate mix homogeneously again, standby;
(2) amodiaquine layer preparation of granules: with wet granulation behind artesunate, microcrystalline Cellulose, polyvidone, the silicon dioxide mix homogeneously, sieve at 40 ℃-55 ℃ dry back 2.0mm, add cross-linking sodium carboxymethyl cellulose, microcrystalline Cellulose and magnesium stearate mix homogeneously again, standby;
(3) tabletting: artesunate layer and amodiaquine layer are placed in respectively in the loading hopper, use the bi-layer tablet press tabletting.
Artesunate of the present invention and amodiaquine hydrochloride bilayer tablet, specification are artesunate 100mg, Camoquin 270mg.
The present invention has following effect:
1, in existing artesunate and the amodiaquine compound preparation preparation process, artesunate all is easy to hydrolysis under acidity or alkali condition, following reaction takes place:
Isopropyl alcohol use in the prepared process in technology and calcium carbonate has suppressed this one-step hydrolysis reaction, has strengthened stability of formulation.
2, the present invention adopts isopropyl alcohol in the wet granulation process, has avoided contacting in technical process water, thereby the control hydrolysis alleviates acid or alkali to esterolytic catalytic action.
3, in preparation process, add calcium carbonate, avoided Camoquin hydrochloric influence, increased stability of formulation.
Description of drawings
Artesunate stripping datagram in Fig. 1 compound preparation
This artesunate stripping curve is at the pH4.5 buffer, obtains under 50 rev/mins of conditions of slurry method, wherein:
Abscissa be dissolution time (minute): length overall is 30 minutes, is spaced apart 5 minutes.
Vertical coordinate is artesunate rate of release (%): length overall is 100, is spaced apart 10.
Camoquin stripping curve figure in Fig. 2 compound preparation
This Camoquin stripping curve is at the pH4.5 buffer, obtains under 50 rev/mins of conditions of slurry method, wherein:
Abscissa be dissolution time (minute): length overall is 30 minutes, is spaced apart 5 minutes.
Vertical coordinate is Camoquin rate of release (%): length overall is 100, is spaced apart 10.
3 months stable accelerated test datagrams of artesunate in Fig. 3 compound preparation
This artesunate stripping curve is at the pH4.5 buffer, obtains under 50 rev/mins of conditions of slurry method, wherein:
Legend key is successively from top to bottom: 0 month, January, February, March.
Abscissa be dissolution time (minute): length overall is 30 minutes, is spaced apart 5 minutes.
Vertical coordinate is artesunate rate of release (%): length overall is 100, is spaced apart 10.
3 months stable accelerated test datagrams of Camoquin in Fig. 4 compound preparation
This Camoquin stripping curve is at the pH4.5 buffer, obtains under 50 rev/mins of conditions of slurry method, wherein:
Legend key is successively from top to bottom: 0 month, January, February, March.
Abscissa be dissolution time (minute): length overall is 30 minutes, is spaced apart 5 minutes.
Vertical coordinate is Camoquin rate of release (%): length overall is 100, is spaced apart 10.
The specific embodiment:
Embodiment 1:
Prescription:
Artesunate layer: artesunate: 100 parts
Calcium carbonate: 50 parts
Pregelatinized Starch: 39.7 parts
Microcrystalline Cellulose: 46.5 parts
Polyvidone: 5.3 parts
Cross-linking sodium carboxymethyl cellulose: 25.2 parts
Magnesium stearate: 2.7 parts
Silicon dioxide: 0.9 part
Amodiaquine layer: Camoquin: 352.6 parts
Microcrystalline Cellulose: 42.3 parts
Cross-linking sodium carboxymethyl cellulose: 26.8 parts
Polyvidone: 19.8 parts
Magnesium stearate: 4.5 parts
Silicon dioxide: 4.0 parts
Preparation:
(4) artesunate layer preparation of granules: with wet granulation behind 100 parts of artesunate, 50 parts of calcium carbonate, 18.1 parts of pregelatinized Starch, 5.3 parts of polyvidones, 3.6 parts of cross-linking sodium carboxymethyl celluloses and the 0.9 part of silicon dioxide mix homogeneously, sieve at 40 ℃ of dry down back 1.4mm, add 21.6 parts of cross-linking sodium carboxymethyl celluloses, 46.5 parts of microcrystalline Cellulose and 2.7 parts of magnesium stearate mix homogeneously again, standby.
(5) amodiaquine layer preparation of granules: with wet granulation behind 352.6 parts of artesunate, 19.8 parts of microcrystalline Cellulose, 19.8 parts of polyvidones, the 4.0 parts of silicon dioxide mix homogeneously, sieve at 50 ℃ of dry down back 2.0mm, add 26.8 parts of cross-linking sodium carboxymethyl celluloses, 22.5 parts of microcrystalline Cellulose and 4.5 parts of magnesium stearate mix homogeneously again, standby.
(6) artesunate layer and amodiaquine layer are put respectively in the loading hopper, used the bi-layer tablet press tabletting.
(7) every heavy 716.8mg in blocks, specification 100mg/270mg
Embodiment 2:
Prescription:
Artesunate layer: artesunate: 100 parts
Calcium carbonate: 50 parts
Pregelatinized Starch: 39.7 parts
Microcrystalline Cellulose: 46.5 parts
Polyvidone: 5.3 parts
Cross-linking sodium carboxymethyl cellulose: 25.2 parts
Magnesium stearate: 2.7 parts
Silicon dioxide: 0.9 part
Amodiaquine layer: Camoquin: 352.8 parts
Microcrystalline Cellulose: 71 parts
Cross-linking sodium carboxymethyl cellulose: 18 parts
Magnesium stearate: 6.8 parts
Silicon dioxide: 3.8 parts
Preparation:
(1) artesunate layer preparation of granules: with wet granulation behind 100 parts of artesunate, 50 parts of calcium carbonate, 18.1 parts of pregelatinized Starch, 5.3 parts of polyvidones, 3.6 parts of cross-linking sodium carboxymethyl celluloses and the 0.9 part of silicon dioxide mix homogeneously, sieve at 40 ℃ of dry down back 1.4mm, add 21.6 parts of cross-linking sodium carboxymethyl celluloses, 46.5 parts of microcrystalline Cellulose and 2.7 parts of magnesium stearate mix homogeneously again, standby.
(2) amodiaquine layer preparation of granules: with wet granulation behind 352.8 parts of artesunate, 18.8 parts of microcrystalline Cellulose, the 3.8 parts of silicon dioxide mix homogeneously, sieve at 50 ℃ of dry down back 2.0mm, add 18.0 parts of cross-linking sodium carboxymethyl celluloses, 52.2 parts of microcrystalline Cellulose and 6.8 parts of magnesium stearate mix homogeneously again, standby.
(3) artesunate layer and amodiaquine layer are put respectively in the loading hopper, used the bi-layer tablet press tabletting.
(4) every heavy 716.5mg in blocks, specification 100mg/270mg
Embodiment 3:
Prescription:
Artesunate layer: artesunate: 100 parts
Calcium carbonate: 50 parts
Pregelatinized Starch: 39.7 parts
Microcrystalline Cellulose: 46.5 parts
Polyvidone: 5.3 parts
Cross-linking sodium carboxymethyl cellulose: 25.2 parts
Magnesium stearate: 2.7 parts
Silicon dioxide: 0.9 part
Amodiaquine layer: Camoquin: 352.7 parts
Microcrystalline Cellulose: 63.3 parts
Polyvidone: 7.7 parts
Cross-linking sodium carboxymethyl cellulose: 18 parts
Magnesium stearate: 6.8 parts
Silicon dioxide: 3.8 parts
Preparation:
(1) artesunate layer preparation of granules: with wet granulation behind 100 parts of artesunate, 50 parts of calcium carbonate, 18.1 parts of pregelatinized Starch, 5.3 parts of polyvidones, 3.6 parts of cross-linking sodium carboxymethyl celluloses and the 0.9 part of silicon dioxide mix homogeneously, sieve at 40 ℃ of dry down back 1.4mm, add 21.6 parts of cross-linking sodium carboxymethyl celluloses, 46.5 parts of microcrystalline Cellulose and 2.7 parts of magnesium stearate mix homogeneously again, standby.
(2) amodiaquine layer preparation of granules: with wet granulation behind 352.7 parts of artesunate, 19.2 parts of microcrystalline Cellulose, 7.7 parts of polyvidones, the 3.8 parts of silicon dioxide mix homogeneously, sieve at 50 ℃ of dry down back 2.0mm, add 18.0 parts of cross-linking sodium carboxymethyl celluloses, 44.1 parts of microcrystalline Cellulose and 6.8 parts of magnesium stearate mix homogeneously again, standby.
(3) artesunate layer and amodiaquine layer are put respectively in the loading hopper, used the bi-layer tablet press tabletting.
(4) every heavy 730.7mg in blocks, specification 100mg/270mg
Embodiment 4:
Prescription:
Artesunate layer: artesunate: 100 parts
Calcium carbonate: 50.1 parts
Pregelatinized Starch: 17.7 parts
Microcrystalline Cellulose: 91.7 parts
Polyvidone: 2.7 parts
Cross-linking sodium carboxymethyl cellulose: 21.6 parts
Magnesium stearate: 2.7 parts
Silicon dioxide: 0.9 part
Amodiaquine layer: Camoquin: 352.8 parts
Microcrystalline Cellulose: 46.9 parts
Polyvidone: 3.8 parts
Cross-linking sodium carboxymethyl cellulose: 36 parts
Magnesium stearate: 6.8 parts
Silicon dioxide: 3.8 parts
Preparation:
(1) artesunate layer preparation of granules: with wet granulation behind 100 parts of artesunate, 50.1 parts of calcium carbonate, 17.7 parts of pregelatinized Starch, 2.7 parts of polyvidones, 9.8 parts of microcrystalline Cellulose and the 0.9 part of silicon dioxide mix homogeneously, sieve at 40 ℃ of dry down back 1.4mm, add 63.8 parts of microcrystalline Cellulose and 2.7 parts of magnesium stearate mix homogeneously again, standby.
(2) amodiaquine layer preparation of granules: with wet granulation behind 352.8 parts of artesunate, 19.0 parts of microcrystalline Cellulose, 3.8 parts of polyvidones, the 3.8 parts of silicon dioxide mix homogeneously, sieve at 50 ℃ of dry down back 2.0mm, add 36.0 parts of cross-linking sodium carboxymethyl celluloses, 27.9 parts of microcrystalline Cellulose and 6.8 parts of magnesium stearate mix homogeneously again, standby.
(3) artesunate layer and amodiaquine layer are put respectively in the loading hopper, used the bi-layer tablet press tabletting.
(4) every heavy 724.4mg in blocks, specification 100mg/270mg.
The dissolution data of the artesunate amodiaquine double-layer tablet prescription that is obtained by experimental example 1-4 is as follows:
Artesunate stripping datagram in Fig. 1 compound preparation;
Amodiaquine stripping curve figure in Fig. 2 compound preparation;
The result shows: the artesunate dissolution reaches more than 75% in 30 minutes, and the amodiaquine dissolution reaches more than 80%, and Chinese Pharmacopoeia artesunate dissolution need reach 60% head and shoulders above, and the amodiaquine dissolution 75% of American Pharmacopeia requirement.
Artesunate amodiaquine compound double-layer preparation to this invention has carried out stable examination simultaneously, 0-3 month stable accelerated test datagram:
3 months stable accelerated test datagrams of artesunate in Fig. 3 compound preparation;
3 months stable accelerated test datagrams of amodiaquine in Fig. 4 compound preparation;
The result shows: in 3 months stable accelerated test, and the stripping data stabilization of artesunate in the double-layer tablet and amodiaquine, substantial conversion does not all take place in wherein active constituents of medicine artesunate and amodiaquine.
Claims (2)
1, a kind of artesunate and amodiaquine hydrochloride bilayer tablet is characterized in that, described double-layer tablet is made up of following raw materials in weight portion:
Artesunate layer: artesunate: 100 parts
Calcium carbonate: 45-55 part
Pregelatinized Starch: 15-45 part
Microcrystalline Cellulose: 40-75 part
Polyvidone: 2.5-5.5 part
Cross-linking sodium carboxymethyl cellulose: 20-30 part
Magnesium stearate: 2.7 parts
Silicon dioxide: 0.8-1 part;
Amodiaquine layer: Camoquin: 352-353 part
Microcrystalline Cellulose: 40-80 part
Polyvidone: 0-30 part
Magnesium stearate: 3-8 part
Silicon dioxide: 3-5 part
2, the preparation method of a kind of artesunate as claimed in claim 1 and amodiaquine hydrochloride bilayer tablet is characterized in that, this method comprises the following steps:
Prescription:
Artesunate layer: artesunate: 100 parts
Calcium carbonate: 45-55 part
Pregelatinized Starch: 15-45 part
Microcrystalline Cellulose: 40-75 part
Polyvidone: 2.5-5.5 part
Cross-linking sodium carboxymethyl cellulose: 20-30 part
Magnesium stearate: 2.7 parts
Silicon dioxide: 0.8-1 part;
Amodiaquine layer: Camoquin: 352-353 part
Microcrystalline Cellulose: 40-80 part
Polyvidone: 0-30 part
Magnesium stearate: 3-8 part
Silicon dioxide: 3-5 part;
Method:
(1) artesunate layer preparation of granules: with wet granulation behind artesunate, calcium carbonate, pregelatinized Starch, polyvidone, cross-linking sodium carboxymethyl cellulose and the silicon dioxide mix homogeneously, sieve at 30 ℃-40 ℃ dry back 1.4mm, add cross-linking sodium carboxymethyl cellulose, microcrystalline Cellulose and 2.7 parts of magnesium stearate mix homogeneously again, standby;
(2) amodiaquine layer preparation of granules: with wet granulation behind artesunate, microcrystalline Cellulose, polyvidone, the silicon dioxide mix homogeneously, sieving at 40 ℃-55 ℃ dry back 2.0mm, add cross-linking sodium carboxymethyl cellulose, microcrystalline Cellulose and magnesium stearate mix homogeneously again, standby;
(3) tabletting: artesunate layer and amodiaquine layer are placed in respectively in the loading hopper, use the bi-layer tablet press tabletting.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200810204298A CN101623270A (en) | 2008-12-10 | 2008-12-10 | Stable artesunate and amodiaquine hydrochloride bilayer tablet and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200810204298A CN101623270A (en) | 2008-12-10 | 2008-12-10 | Stable artesunate and amodiaquine hydrochloride bilayer tablet and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101623270A true CN101623270A (en) | 2010-01-13 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200810204298A Pending CN101623270A (en) | 2008-12-10 | 2008-12-10 | Stable artesunate and amodiaquine hydrochloride bilayer tablet and preparation method thereof |
Country Status (1)
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|---|---|
| CN (1) | CN101623270A (en) |
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- 2008-12-10 CN CN200810204298A patent/CN101623270A/en active Pending
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Open date: 20100113 |