| Angina pectoris belongs to the category of “obstruction of qi in the chest”, “cardiodynia” of traditional Chinese medicine, the pathogenesis of deficiency in origin and excess in superficiality, while qi deficiency and blood stasis type of coronary heart disease(CHD) is the most common type. “Yixinshu” formulation derives from medical origins of “Shengmai San” add drugs, which is beneficial for gas pulse, promoting blood circulation to remove blood stasis, nourishing yin fluid effect, and is commonly used for the thoracic obstruction caused by qi and yin deficiency and blood stasisi in viens, which are seen chest tightness and uncomfortable, heart palpitations and shortness of breath, pulse knot generation. And it is also uesd for angina pectoris as the above symptoms. “Yixinshu” formulation could be effective, safe and reliable in the treatment of qi deficiency and blood stasis type of CHD.The common dosage forms of “Yixinshu” include capsules, tablets and other oral solid preparations, with the problem of long disintegration time and slow dissolution, which cause working slowly. Dispersible tablets as an oral rapiad-release solid dosage form has the advantages of tablets and liquid prepartions. It is easy-taken and has short disintegration time, rapid drug dissolution, rapid absorption and high bioavailability. This paper proposes the preparation of Yixinshu dispersible tablets to shorten the disintegration time, improve bioavailability, and achieve rapid effect, in order to relieve the symptoms of the thoracic obstruction, play a better effect for the treatment of qi deficiency and blood stasis type of CHD and impove the patients quality of life.Objetctive:1. To research Yixinshu extraction process;2. To study Yixinshu extract spray drying process;3. To study Yixinshu dispersible tablets molding process;4. To establish Yixinshu dispersible tablets quality evaluation.Methods:1.(1)The content of ginsenoside Re, Rg1 and Rb1 was determined by HPLC-ELSD. With the transfer rate of Rg1 & Re ginsenosides, ginsenoside Rb1 and the extract rate as the index, single-factor test and orthogonal test were used to optimize the ginseng alcohol extraction.(2)The content of tanshinoneⅡA and schizandrol was analyzed by HPLC. Taking tanshinoneⅡA transfer rate, schizandrol transfer rate and the extract rate as the index, single-factor test and orthogonal test were used to optimize Salvia and Schisandra alcohol extraction process.(3)The content of astragaloside was carried out by HPLC-ELSD. Single-factor test and orthogonal test were used for the optimum of water extracting-alcohol precipitating process, with astragaloside transfer rate and the extract rate as the index.2. With flour yield and moisture content of spray drying powder as the index, uniform design was used to optimize the spray drying process parameters of Yixinshu extract.3. Using the dispersed homogeneous time as the index, single-factor design was used to select the types of fillers and disintegrants, and the combination of different disintegrants. The central composite design-response surface method was used to optimize the dosages of MCC, L-HPC, cCMC-Na and determine the optimal prescription of Yixinshu dispersible tablets.4. The qualitative identification methods of “Yixinshu” formulation in the Chinese pharmacopoeia 2015 edition(vol.Ⅰ) were used to distinguish ginseng, astragalus, salvia miltiorhiza, schisandra chinensis and dwarf lilyturf. The determination of ginsenosides Rg1, Re, Rb1, Rd and astragaloside was established by HPLC-ELSD. The conent of tanshinoneⅡA and schizandrol was determined by HPLC. The dissolution test method of ginsenosides Rg1, Re, Rb1, tanshinoneⅡA and schizandrol was established.Results:1. Yixinshu extraction process:(1) The optimum ginseng alcohol extraction process was 6 times of 70% ethanol, extracting for 2h, for 3 times.(2) The optimum alcohol extraction process of salvia miltiorhiza and schisandra chinensis was 6 times of 85% ethanol, extracting for 1.5h, for twice.(3) The optimum water extracting-alcohol precipitating process of astragalus, hawthorn and rhizoma ligustici wallichii was 6 times of water, extracting for 1.5h, for 3 times. And then the extracts were combined and concentrated to the relative density of 1.12(60℃),adding 1.5 times of 85% ethanol, stirred well and standed 8-20 h.2. The best spray drying process of Yixinshu extract was as follows: inlet velocity was 10.5mL·min-1, inlet air temperature was 190℃, outlet air temperature was 85℃ and relative density of the liquid was 1.05(60℃).3. The optimum forming process of Yixinshu dispersible tablets: powder 27%, MCC 54%, L-HPC 9%, cCMC-Na 8%, magnesium stearate 1%, mico-silica 1%, through 100 m screen mesh and fully-mixed, by powder direct compression, and hardness controlled at 4-5kg.4. The qualitative identifications of ginseng, astragalus, salvia miltiorhiza, schisandra chinensis and dwarf lilyturf were exclusive, no negative interference. The content of ginsenosides Re, Rg1, Rb1, Rd and astragaloside in Yixinshu dispersible tablets were determined by HPLC-ELSD, with acetonitrile-water gradient, drift tube temperature 85℃, gas flow rate measurement 1L·min-1. The schisandrin content was analyzed with methanol-water gradient elution, detection wavelength 250 nm, column temperature 30℃. The tanshinoneⅡA schisandrin content in Yixinshu dispersible tablets was measured with acetonitrile-water(60:40, v/v), detection wavelength 270 nm, column temperature 30℃. The ginsenosides Re, Rg1 and Rb1 dissolution was tested with 100 mL of purified water and 50r·min-1 as the speed. When 15 min, cumulative dissolution rate was above 80%, 80%, 90% and achieve relsase drugs quickly. The schizandrol dissolution was carried out with 250 mL of purified water and 50r·min-1 as the speed. When 15 min, cumulative dissolution rate was above 80% and achieve relsase drugs quickly. The tanshinoneⅡA dissolution was analyzed with 250 mL of 0.5% SDS aqueous and 75r·min-1 as the speed. When 15 min, cumulative dissolution rate was above 70% and achieve relsase drugs quickly.Conclution:Yixinshu extraction process has low extract rate, and is suitable for further formulation research. Preparation process is stable, scientific, suitable for industrial production. Quality evaluation methods can effectively control the quality of Yixinshu dispersible tablets. |
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