US20160151293A1 - Formulation of a micro drop pill and the preparation method thereof - Google Patents

Formulation of a micro drop pill and the preparation method thereof Download PDF

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Publication number
US20160151293A1
US20160151293A1 US14/903,896 US201414903896A US2016151293A1 US 20160151293 A1 US20160151293 A1 US 20160151293A1 US 201414903896 A US201414903896 A US 201414903896A US 2016151293 A1 US2016151293 A1 US 2016151293A1
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Prior art keywords
drop pill
dropping
peg
temperature
dripper
Prior art date
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Abandoned
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US14/903,896
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English (en)
Inventor
Xijun Yan
Naifeng Wu
Kaijing Yan
Xiaobing Sun
Shunnan Zhang
Zhengliang Ye
Hai'ou Dong
Hongbo Zhang
Wensheng ZHANG
Lihong Zhou
Chenming Li
Cong Chen
Xiaofeng Liu
Shiqing Wang
Changsheng Rong
Yongfeng Zheng
Lijun FAN
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Tasly Pharmaceutical Group Co Ltd
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Tasly Pharmaceutical Group Co Ltd
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Priority claimed from CN201310290966.9A external-priority patent/CN104274319A/zh
Priority claimed from CN201310290967.3A external-priority patent/CN104274517B/zh
Priority claimed from CN201310291465.2A external-priority patent/CN104274416B/zh
Application filed by Tasly Pharmaceutical Group Co Ltd filed Critical Tasly Pharmaceutical Group Co Ltd
Assigned to TASLY PHARMACEUTICAL GROUP CO., LTD. reassignment TASLY PHARMACEUTICAL GROUP CO., LTD. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CHEN, Cong, DONG, Hai'ou, FAN, LIJUN, LI, Chenming, LIU, XIAOFENG, RONG, Changsheng, SUN, XIAOBING, WANG, Shiqing, WU, NAIFENG, YAN, KAIJING, YAN, XIJUN, YE, ZHENGLIANG, ZHANG, HONGBO, ZHANG, SHUNNAN, ZHANG, WENSHENG, ZHENG, YONGFENG, ZHOU, LIHONG
Publication of US20160151293A1 publication Critical patent/US20160151293A1/en
Abandoned legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J3/00—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
    • A61J3/06—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms into the form of pills, lozenges or dragees
    • A—HUMAN NECESSITIES
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    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/25—Araliaceae (Ginseng family), e.g. ivy, aralia, schefflera or tetrapanax
    • A61K36/258—Panax (ginseng)
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    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Definitions

  • the present invention relates to a preparation method of a traditional Chinese medicine (TCM) micro drop pill and TCM micro drop pill prepared by using the method, more particularly, the present invention relates to a micro drop pill preparation method with high drug-loading capacity, simple preparation process and high production rate and a micro drop pill prepared by the method.
  • the method can be used to prepare an uncoated micro drop pill, a coated micro drop pill and a micro drop pill capsule with high drug-loading capacities.
  • Drop pill as an important traditional Chinese medicine preparation, has been used widely. In practice, it has the following merits: shortened production cycle, dust pollution-free, high bioavailability, rapid onset of effect, prolonged action in topical administration, reduced volatility of drug, increased drug stability and being easily carried and stored.
  • the preparation method of the traditional drop pill is to drop a molten medicine liquid into an immiscible cooling medium (in most cases, a coolant is used as the cooling medium) to give the drop pill.
  • a coolant is used as the cooling medium.
  • the unit drug-loading capacity is small (usually, the drug-loading capacity of the active pharmaceutical ingredient (API) is only about 25 wt %) and the amount of matrix used is very large. This cannot meet the requirement of international market that the maximum daily dosage of polyethylene glycols (PEGs) matrix should not exceed 700 mg.
  • the objective of the present invention is to provide a simple and high-speed preparation method to prepare a micro drop pill with high drug-loading capacity and small amount of matrix.
  • the preparation method for preparing the micro drop pill comprises the following steps:
  • Material melting step heat melting a medicine and a drop pill matrix to obtain a molten medicine liquid
  • Another objective of the present invention is to provide a TCM micro drop pill.
  • the ratio of the medicine to the drop pill matrix is 1:5 ⁇ 5:1 by weight, and the particle size of the micro drop pill is 0.2 mm ⁇ 4 mm.
  • the micro drop pill is prepared according to the preparation method of the micro drop pill of the present invention, and there is no residual coolant.
  • the micro drop pill means that the micro drop pill has a smaller particle size compared with the traditional drop pill. More specifically, the micro drop pill refers to the one with a particle size of 0.2 mm ⁇ 4 mm, especially, the one with a particle size of 0.2 mm ⁇ 2 mm, preferably 1 mm ⁇ 2 mm.
  • the coolant of the drop pill means the coolant commonly-used in the preparation of the traditional drop pill, for example, but not limited to, liquid paraffin, methyl silicone oil and plant oil (soybean oil and castor oil etc.).
  • the medicine includes any one of TCMs or chemicals that is suitable to be prepared into the drop pills.
  • the extract is preferred to be used, e.g. Ginkgo Biloba extract, Bupleurum extract, Salvia Militiorrhiza extract and Andrographis Paniculata extract, as well as the extracts of Qishenyiqi, Huoxiangzhengqi and Compound Salvia Militiorrhiza .
  • These extracts can either be commercially available, or prepared by the method known in the prior art.
  • the micro drop pill includes, but is not limited to: Compound Salvia Militiorrhiza micro drop pill (CSMDP), Qishenyiqi micro drop pill (QMDP), Salvia Militiorrhiza micro drop pill (SMDP), Huoxiangzhengqi micro drop pill (HMDP), Andrographis Paniculata micro drop pill (AMDP), Compound Ginkgo Biloba micro drop pill (CGMDP), Guanxindanshen micro drop pill (GMDP) and Xuesaitong micro drop pill (XMDP) etc.
  • the medicines in the present invention are the API of Compound Salvia Militiorrhiza and the API of Qishenyiqi.
  • Another objective of the present invention is to provide Compound Salvia Militiorrhiza micro drop pill prepared by the method of the present invention, characterized in that the ratio of the API of Compound Salvia Militiorrhiza to the drop pill matrix is 1:5 ⁇ 5:1 by weight, and a particle size of the micro drop pill is 0.2 mm ⁇ 4 mm, preferably 0.2 mm ⁇ 2 mm, more preferably 1 mm ⁇ 2 mm.
  • the API of Compound Salvia Militiorrhiza is prepared with the following crude drugs by weight parts: Salvia Militiorrhiza 75.0 ⁇ 90.0 parts, Panax Notoginseng 10.0 ⁇ 25.0 parts and borneol 0.1 ⁇ 4.0 parts, and is prepared by the preparation method for the micro drop pill of the present invention. There is no residual coolant in the micro drop pills.
  • Another objective of the present invention is to provide QMDP (Qishenyiqi micro drop pill) prepared by the method of the present invention, characterized in that the ratio of the API of Qishenyiqi to the drop pill matrix is 1:5 ⁇ 5:1 by weight, and the particle size 0.2 mm ⁇ 4 mm, preferably 0.2 mm ⁇ 2 mm, more preferably 1 mm ⁇ 2 mm.
  • the API of Qishenyiqi is prepared by the following crude drugs by weight parts: Astragalus membranaceus 100 ⁇ 200 parts, Salvia Militiorrhiza 50 ⁇ 100 parts, Panax Notoginseng 10 ⁇ 20 parts and volatile oil from Lignum Dalbergiae Odoriferae 0.5 ⁇ 2 parts, and is prepared by the preparation method for the micro drop pill of the present invention. There is no residual coolant in the micro drop pills.
  • the present invention is achieved by the following technical solutions:
  • a preparation method for a micro drop pill comprising the following steps:
  • Material melting step heat melting a medicine and a drop pill matrix to obtain a molten medicine liquid
  • Material melting step heat melting the medicine and the drop pill matrix at 40° C. ⁇ 120° C., homogenizing for 0.5 ⁇ 4 hours to obtain a homogenized molten medicine liquid, and the ratio of the medicine to the drop pill matrix is 1:5 ⁇ 5:1 by weight;
  • Condensation step cooling the medicine drops with a cooling gas for forming by solidifying, obtaining micro drop pills having a particle size of 0.2 mm ⁇ 4 mm, the temperature of the cooling gas is 0° C. or lower.
  • the drop pill matrix includes one or more selected from the group consisting of PEGs, sorbitol, xylitol, lactitol, maltose, starch, methylcellulose, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose (HPMC), arabic gum, alginic acid, dextrin, cyclodextrin, agar and lactose; preferably solid PEGs, such as PEG-1000, PEG-2000, PEG-3000, PEG-4000, PEG-5000, PEG-6000, PEG-7000 and PEG-8000; more preferably one or more selected from the group consisting of PEG-1000, PEG-2000, PEG-3000, PEG-4000, PEG-6000 and PEG-8000; most preferably PEG-6000, PEG-4000 or the combination of PEG-4000 and PEG-6000.
  • PEGs sorbitol, xylitol, lactitol, maltose, starch, methylcellulose
  • Step (1) the temperature for heat melting is at 60 ⁇ 100° C., more preferably at 65 ⁇ 90° C., further preferably 75 ⁇ 85° C.
  • the homogenizing time preferably is 1 ⁇ 3 hours, further preferably 2 hours.
  • Step (1) the ratio of the medicine to the drop pill matrix is 1:3 ⁇ 3:1 by weight, preferably 1: (1 ⁇ 3) by weight.
  • Step (2) the temperature of the dripper is at 40 ⁇ 120° C., preferably at 40 ⁇ 100° C.; the vibration frequency for dropping is preferably at 20 ⁇ 300 Hz, more preferably 50 ⁇ 300 Hz, more preferably 20 ⁇ 200 Hz, more preferably 20 ⁇ 150 Hz, most preferably 50 ⁇ 150 Hz; the vibration mode includes magnetic/electronic vibration or pneumatic vibration.
  • Step (3) the temperature of the cooling gas is at 0° C. ⁇ 150° C., preferably ⁇ 10 ⁇ 140° C., further preferably ⁇ 40° C. ⁇ 140° C., further preferably ⁇ 60° C. ⁇ 140° C., most preferably ⁇ 80° C. ⁇ 120° C.; and the cooling gas is air, nitrogen or inert gas.
  • Step (3) the particle size of the micro drop pill is 1.0 mm ⁇ 2.0 mm, preferably 0.5 mm ⁇ 2 mm.
  • Material melting step heat melting the medicine and the drop pill matrix at 60° C. ⁇ 100° C., homogenizing for 1 ⁇ 3 hours to obtain a homogenized molten medicine liquid, the ratio of the medicine to the drop pill matrix is 1:3 ⁇ 3:1 by weight;
  • Material melting step charging the medicine and the drop pill matrix into a homogenizer, mixing homogenously at 1000 ⁇ 5000 rpm for 1 ⁇ 200 min, then melting homogenously at 3000 ⁇ 10000 rpm for 1 ⁇ 100 min; during the melting process, the temperature is kept at 60 ⁇ 100° C. to obtain the molten medicine liquid; the ratio of the medicine to the drop pill matrix is 1:5 ⁇ 5:1 by weight;
  • Step (2) Dropping step: delivering the molten medicine liquid under pressure to the dripper, and acquiring medicine drops from the dripper by means of vibration dropping at a vibration frequency of 20 ⁇ 300 Hz under a dropping pressure of 0.5 ⁇ 4.0 Bar and the temperature of the dripper of 40° C. ⁇ 200° C., the dropping rate is matched with the melting rate in Step (1);
  • Step (1) the ratio of the medicine to the drop pill matrix is 1:3 ⁇ 3:1 by weight, mixing homogeneously at 3000 ⁇ 5000 rpm for 10 ⁇ 60 min, then melting homogeneously at 4000 ⁇ 9000 rpm for 5 ⁇ 30 min, during the melting process, the temperature is kept at 70 ⁇ 90° C.
  • Step (1) the ratio of the medicine to the drop pill matrix is 1:(1 ⁇ 3) by weight, mixing homogeneously at 3000 ⁇ 4000 rpm for 10 ⁇ 30 min, then melting homogeneously at 4000 ⁇ 6000 rpm for 6 ⁇ 30 min, during the melting process, the temperature is kept at 75 ⁇ 85° C.
  • Step (2) the temperature of the dripper is at 70 ⁇ 100° C.
  • the vibration frequency for dropping is at 90 ⁇ 200 Hz
  • the dropping pressure is at 1.0 ⁇ 3.0 Bar; preferably the vibration frequency is at 137 Hz, an acceleration speed is at 4G, the dropping pressure is at 1.8 Bar and the temperature of the dripper is at 75 ⁇ 85° C.
  • the dropping rate is 10 ⁇ 40 Kg/h, preferably 12 ⁇ 30 Kg/h, further preferably 15 ⁇ 25 Kg/h.
  • Step (4) drying the low-temperature drop pills from Step (3) on a fluidized-bed at 40 ⁇ 150° C., preferably at 40 ⁇ 60° C. for 1 ⁇ 4 hours, preferably 1 ⁇ 3 hours, most preferably 2 hours to obtain uncoated drop pills.
  • Step (4) a gradient-rising temperature drying method is used as follows: fluidizing at ⁇ 20 ⁇ 30° C., drying at 15 ⁇ 35° C. for 10 ⁇ 120 min, drying at 35 ⁇ 55° C. for 10 ⁇ 60 min, drying at 55 ⁇ 100° C. for 0 ⁇ 60 min; preferably, the gradient-rising temperature drying method is performed as follows: fluidizing at 0 ⁇ 20° C., drying at 25° C. for 60 min, drying at 45° C. for 30 min, drying at 55° C. for 0 ⁇ 30 min.
  • the method additionally comprises a coating step as Step (5): coating the uncoated drop pills obtained from Step (4) in a state of fluidization; the concentration of the coating liquid is at 15 ⁇ 25 wt %, preferably 18 ⁇ 20 wt %; the coating material is selected from shellac, CAP (cellulose acetate phthalate), methyl acrylate, methyl methacrylate or Opadry; the ratio of the coating material to the uncoated drop pill is 1:50 ⁇ 1:25 by weight.
  • a coating step as Step (5) coating the uncoated drop pills obtained from Step (4) in a state of fluidization; the concentration of the coating liquid is at 15 ⁇ 25 wt %, preferably 18 ⁇ 20 wt %; the coating material is selected from shellac, CAP (cellulose acetate phthalate), methyl acrylate, methyl methacrylate or Opadry; the ratio of the coating material to the uncoated drop pill is 1:50 ⁇ 1:25 by weight.
  • the present invention includes the following technical solutions:
  • a TCM micro drop pill wherein in the micro drop pill, the ratio of the medicine to the drop pill matrix is 1:5 ⁇ 5:1 by weight, a particle size of the micro drop pill is 0.2 mm ⁇ 4 mm, the micro drop pill is prepared by any one method of the 1 st ⁇ 19 th paragraphs, and the micro drop pill has no residual coolant.
  • the TCM micro drop pill according to the 20 th paragraph characterized in that the particle size is 0.2 mm ⁇ 2 mm.
  • the TCM micro drop pill according to the 21 st paragraph characterized in that the particle size is 1 mm ⁇ 2 mm.
  • a Compound Salvia Militiorrhiza micro drop pill wherein the micro drop pill is prepared by the API of Compound Salvia Militiorrhiza and the drop pill matrix in a ratio of 1:5 ⁇ 5:1 by weight, the particle size of the Compound Salvia Militiorrhiza micro drop pill is 0.2 mm ⁇ 4 mm, the API of Compound Salvia Militiorrhiza is prepared by the following crude drugs by weight parts: Salvia Militiorrhiza 75.0 ⁇ 90.0 parts, Panax Notoginseng 10.0 ⁇ 25.0 parts and borneol 0.1 ⁇ 4.0 parts, and the micro drop pill is prepared by any one method of the 1 st ⁇ 19 th paragraphs, and the micro drop pill has no residual coolant.
  • CSMDP Compound Salvia Militiorrhiza micro drop pill
  • micro drop pill is prepared by the API of Compound Salvia Militiorrhiza and the drop pill matrix in a ratio of 1:3 ⁇ 3:1 by weight.
  • micro drop pill is prepared by the API of Compound Salvia Militiorrhiza and the drop pill matrix in a ratio of 1: (1 ⁇ 3) by weight.
  • a Qishenyiqi micro drop pill characterized in that the micro drop pill is prepared by the API of Qishenyiqi and the drop pill matrix in a ratio of 1:5 ⁇ 5:1 by weight, the particle size of the Qishenyiqi micro drop pill is 0.2 mm ⁇ 4 mm, the API is prepared by the following crude drugs by weight parts: Astragalus membranaceus 100 ⁇ 200 parts, Salvia Militiorrhiza 50 ⁇ 100 parts, Panax Notoginseng 10 ⁇ 20 parts and volatile oil from Lignum Dalbergiae Odoriferae 0.5 ⁇ 2 parts, the micro drop pill is prepared by any one method of the 1 st ⁇ 19 th paragraphs, and the micro drop pill has no residual coolant.
  • QMDP Qishenyiqi micro drop pill
  • the preparation method for preparing the micro drop pill comprises the following steps:
  • Material melting step heat melting the medicine and the drop pill matrix at 40° C. ⁇ 120° C., homogenizing for 0.5 ⁇ 4 hours to obtain a homogenized molten medicine liquid, the ratio of the medicine to the drop pill matrix is 1:5 ⁇ 5:1 by weight;
  • the drop pill matrix includes one or more selected from the group consisting of PEGs, sorbitol, xylitol, lactitol, maltose, starch, methylcellulose, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose (HPMC), arabic gum, alginic acid, dextrin, cyclodextrin, agar and lactose, preferably solid PEGs, such as PEG-1000, PEG-2000, PEG-3000, PEG-4000, PEG-5000, PEG-6000, PEG-7000 and PEG-8000, more preferably one or more selected from the group consisting of PEG-1000, PEG-2000, PEG-3000, PEG-4000, PEG-6000, PEG-8000, most preferably PEG-6000, PEG-4000 or the combination of PEG-4000 and PEG-6000.
  • PEGs sorbitol, xylitol, lactitol, maltose, starch, methylcellulose
  • the temperature for heat melting preferably is at 60 ⁇ 100° C., more preferably at 65 ⁇ 90° C., further preferably 75 ⁇ 85° C.
  • the homogenizing time preferably is 1 ⁇ 3 hours, further preferably 2 hours.
  • the ratio of the medicine to the drop pill matrix is 1:3 ⁇ 3:1 by weight, preferably 1:(1 ⁇ 3) by weight.
  • the temperature of the dripper is preferably at 60 ⁇ 120° C., preferably at 60 ⁇ 100° C.; the vibration frequency for dropping is preferably at 20 ⁇ 300 Hz, more preferably 50 ⁇ 300 Hz, more preferably 20 ⁇ 200 Hz, more preferably 20 ⁇ 150 Hz, most preferably 50 ⁇ 150 Hz.
  • the vibration mode includes magnetic/electronic vibration or pneumatic vibration. Wherein, in the pneumatic vibration mode, the vibration frequency and the vibration amplitude are larger. If the material viscosity is more than 800 cp, the electronic vibration is incapable of effectively cutting material, resulting in the blockage of the dripper; if this happens, the pneumatic vibration mode can be used.
  • the electronic vibration is preferably employed, the viscosity of the molten medicine liquid preferably is 500 ⁇ 1000 cp, more preferably 700 ⁇ 1000 cp.
  • a vibration waveform is used as a PAT (Process Analyzing Technology) index to measure the distribution of the particle size and to monitor the state of fluidization of the drop pills in the real-time manner by using a stroboscopic device.
  • PAT Process Analyzing Technology
  • the condensation by a cooling gas means that the drops are cooled by using a low-temperature condensate trap to form by solidifying.
  • the temperature of the cooling gas is at 0° C. ⁇ 150° C., preferably ⁇ 10° C. ⁇ 140° C., further preferably ⁇ 40° C. ⁇ 140° C., further preferably ⁇ 60° C. ⁇ 140° C., most preferably ⁇ 80° C. ⁇ 120° C.;
  • the cooling gas is air, nitrogen or inert gas;
  • the particle size of the micro drop pill is 1.0 mm ⁇ 2.0 mm, preferably 0.5 mm ⁇ 2 mm.
  • the preparation method for preparing the micro drop pill comprises the following steps:
  • Material melting step heat melting the medicine and the drop pill matrix at 60° C. ⁇ 100° C., homogenizing for 1 ⁇ 3 hours to obtain a homogenized molten medicine liquid, the ratio of the medicine to the drop pill matrix is 1:3 ⁇ 3:1 by weight;
  • the preparation method for preparing the micro drop pill comprises the following steps:
  • Material melting step charging the medicine and the drop pill matrix into a homogenizer, mixing homogenously at 1000 ⁇ 5000 rpm for 1 ⁇ 200 min, then melting homogenously at 3000 ⁇ 10000 rpm for 1 ⁇ 100 min; during the melting process, the temperature is kept at 60 ⁇ 100° C. to obtain the molten medicine liquid; the ratio of the medicine to the drop pill matrix is 1:5 ⁇ 5:1 by weight;
  • Step (2) Dropping step: delivering the molten medicine liquid to a dripper, and acquiring medicine drops by means of vibration dropping at a vibration frequency for dropping of 20 ⁇ 300 Hz under a dropping pressure of 0.5 ⁇ 4.0 Bar and the temperature of the dripper of 40° C. ⁇ 200° C.; the dropping rate is matched with the melting rate in Step (1); and,
  • the ratio of the medicine to the drop pill matrix is 1:3 ⁇ 3:1 by weight, mixing homogeneously 3000 ⁇ 5000 rpm for 10 ⁇ 60 min and melting homogeneously at 4000 ⁇ 9000 rpm for 5 ⁇ 30 min, during the melting process, the temperature is kept at 70 ⁇ 90° C.; most preferably, the ratio of the medicine to the drop pill matrix is 1:(1 ⁇ 3) by weight, mixing homogeneously 3000 ⁇ 4000 rpm for 10 ⁇ 30 min and melting homogeneously at 4000 ⁇ 6000 rpm for 6 ⁇ 30 min, during the melting process, the temperature is kept at 75 ⁇ 85° C.
  • the temperature of the dripper is at 70 ⁇ 100° C.
  • the vibration frequency for dropping is at 90 ⁇ 200 Hz
  • the dropping pressure is at 1.0 ⁇ 3.0 Bar
  • the vibration frequency is at 137 Hz
  • the acceleration speed is at 4G
  • the dropping pressure is at 1.8 Bar
  • temperature of the dripper is at 75 ⁇ 85° C.
  • the dropping rate is 10 ⁇ 40 Kg/h, preferably 12 ⁇ 30 Kg/h, further preferably 15 ⁇ 25 Kg/h.
  • the method can additionally comprise a drying step as Step (4): drying the low-temperature drop pills from Step (3) on a fluidized-bed at 40 ⁇ 150° C., preferably at 40 ⁇ 60° C. for 1 ⁇ 4 hours, preferably 1 ⁇ 3 hours, most preferably 2 hours to obtain the uncoated drop pills.
  • Step (4) drying the low-temperature drop pills from Step (3) on a fluidized-bed at 40 ⁇ 150° C., preferably at 40 ⁇ 60° C. for 1 ⁇ 4 hours, preferably 1 ⁇ 3 hours, most preferably 2 hours to obtain the uncoated drop pills.
  • a gradient-rising temperature drying method is used as follows: fluidizing at ⁇ 20 ⁇ 30° C., drying at 15 ⁇ 35° C. for 10 ⁇ 120 min, drying at 35 ⁇ 55° C. for 10 ⁇ 60 min, drying at 55 ⁇ 100° C. for 0 ⁇ 60 min; preferably, the gradient-rising temperature drying method is performed as follows: fluidizing at 0 ⁇ 20° C., drying at 25° C. for 60 min, drying at 45° C. for 30 min, drying at 55° C. for 0 ⁇ 30 min.
  • Step (4) by screening from a large number of drying methods, the inventors found that: in Step (3), the uncoated drop pill is dried by one of the following drying methods: airing under low-humidity, drying by coating pot, drying by vacuum drying oven, drying by hot air circulation drying oven, drying by track type microwave dryer, drying by fluidized drying coater.
  • airing under low-humidity drying by coating pot, drying by vacuum drying oven, drying by hot air circulation drying oven, drying by track type microwave dryer, drying by fluidized drying coater.
  • drying by coating pot, drying by track type microwave dryer, drying by fluidized drying coater are preferred.
  • drying by fluidized-bed is preferred, and drying by fluidized drying coater is more preferred. Advantages and disadvantages of various drying methods are shown in Table 1.
  • the yield (1) Demanding the inlet air having a low coating pot is usually about 95% humidity, generally no more than 5 g/kg; without considering the (2) Low drying efficiency, at least 6 h/batch; effect of dropping factor; (3) Custom-made device; (2) Drying and coating (4) Easily resulting in product rejection due to can be achieved in one the adhesion of drop pills. machine. 3 Drying by None (1) Low drying efficiency, demanding low- vacuum temperature vacuum drying for a long time, at drying oven least 30 h/batch; (2) Low-productivity device, the productivity of oven per square meter is difficult to exceed 0.2 kg/h; (3) hardly resulting in adhesion and deformation of drop pills, which is not round in appearance.
  • the preparation method for the micro drop pill can additionally comprise a coating step as Step (5): coating the uncoated drop pills obtained from Step (4) in a state of fluidization; the concentration of the coating liquid is at 15 ⁇ 25 wt %, preferably 18 ⁇ 20 wt %; the coating material is selected from shellac, CAP (cellulose acetate phthalate), methyl acrylate, methyl methacrylate or Opadry; the ratio of the coating material to the uncoated drop pills is 1:50 ⁇ 1:25 by weight.
  • a coating step (5) coating the uncoated drop pills obtained from Step (4) in a state of fluidization; the concentration of the coating liquid is at 15 ⁇ 25 wt %, preferably 18 ⁇ 20 wt %; the coating material is selected from shellac, CAP (cellulose acetate phthalate), methyl acrylate, methyl methacrylate or Opadry; the ratio of the coating material to the uncoated drop pills is 1:50 ⁇ 1:25 by weight
  • the method in order to better implement the preparation method for the micro drop pill, preferably, can additionally comprise a pre-mixing step before Step (1): adding the medicine powder or extract with water, stirring for 10 min or longer at 30 ⁇ 80° C. to obtain a pre-mixed medicine material, ensuring the homogenization of water content.
  • This step can remedy the defects brought about by feeding dried powder material.
  • the micro drop pills prepared by the method can be either packaged directly, or prepared into capsule after loading into a capsule shell.
  • the weighing step for capsules one-by-one may be additionally employed. Before packaging, high-speed weighing for the loaded capsules one-by-one is employed so as to eliminate possibly unqualified capsules.
  • the features of the method are as follows: it is the first time to combine the techniques of vibration dropping and gas cooling with the fluidized drying & coating method creatively and apply to the preparations of drop pills and drop pill capsules. Hence, both producing rate and forming quality of the drop pill are increased. Further the production process is simplified.
  • the advantages of the present invention are presented as follows:
  • Utilization of gas cooling well meets the requirements of high-speed dropping, preparing a micro drop pill (with a particle size of 2.5 mm or smaller) and increasing drug-loading capacity.
  • the drug-loading capacity of the drop pill has been increased by folds while the amount of the drop pill matrix and the dosage are reduced dramatically.
  • the productivity of the drop pills has been enhanced greatly from the traditional rate of 1 ⁇ 2 pills/s to 1000 ⁇ 1250 pills/s, and the range of the particle size is expanded from 2 mm ⁇ 4 mm to 0.2 mm ⁇ 4 mm. It is possible to produce the micro drop pills that can better meet the requirements for capsule loading.
  • the vibration parameters and fluidized drug loading coating the drug-loading capacity can be increased from about 25 wt % of the traditional drop pills to 50 wt % and higher, and the amount of the drop pill matrix is also reduced by leaps and bounds.
  • fluidized drying & coating process not only can solve the problems during the storage of the drop pills prepared by air drying method such as possible adhesion of the drop pills from each other, precipitation of components and reduced volatile oil components, but also the drying time can be reduced from 4 ⁇ 24 hours to only 2 hours.
  • the molten medicine liquid was injected to make drug-loading coating, and the drug-loading capacity can be further increased.
  • this technique of injection can be used for coating the drop pills so as to realize the purposes of different techniques (e.g. sustained release coating, film coating and sugar coating etc). Because the fluidization is a mild process, it ensures the water content in the drop pill reaches a stable value, and the uniformity in drug-loading and coating in the drop pills are also improved. Unlike the drop pills prepared by the traditional methods, the fluidization can prevent the drop pills from being cleft and white-dotted, and at the same time, the yield is increased.
  • capsule coolant the material
  • shell increasing reduced pill dropping weight makes rate, greatly the filling improving amount more the accurate preparation when being efficiency. filled into capsule, drug release rate is also accelerated, and thus a clinical efficacy is improved.
  • Commercially Larger Drug- Residual Slower Better available pill loading coolant on dropping roundness, drop pills weight, 18 ⁇ 20 wt % the surface rate than that the drop pill 25 mg ⁇ 27 (calculated of the drop of the with a mg based on pills vibration particle size dried dropping, of extract) and 1 mm ⁇ 2 mm complicated cannot be process of prepared. eliminating the coolants on the surface of the drop pills, time- consuming process.
  • Compound Salvia Militiorrhiza Drop Pill is a TCM developed by Tianjin Tasly Pharmaceutical Co., Ltd, which is proven to have effects of activating blood by removing stasis and stopping pain by regulating Qi, used for treating chest distress and angina pectoris.
  • the main ingredients of Compound Salvia Militiorrhiza Drop Pill include Salvia Militiorrhiza, Panax Notoginseng and borneol. Its pharmacological effects include increasing coronary blood flow, protecting ischemia myocardium by strengthening hypoxia tolerance, preventing thrombosis by anti-platelet aggregation and improving microcirculation etc.
  • the current Compound Salvia Militiorrhiza Drop Pill was prepared by the following method: extracting Salvia Militiorrhiza and Panax Notoginseng with water to give an extraction liquid, which was followed by concentration to get the extract; mixing the extract with the drop pill matrix, delivering to a dropping machine, into which borneol was added and well mixed to get a material; melting and dropping the material, and cooling the medicine drops by using liquid paraffin as a coolant to obtain Compound Salvia Militiorrhiza Drop Pill.
  • the preparation of Compound Salvia Militiorrhiza Drop Pill was known as a very mature technique by the person skilled in the art, there were still a lot of problems faced during the preparation process, e.g. large amount of the matrix and a small unit drug-loading capacity.
  • the CSMDP is prepared by the API of Compound Salvia Militiorrhiza and the drop pill matrix in a ratio of 1:5 ⁇ 5:1 by weight; preferably 1:3 ⁇ 3:1 by weight; most preferably 1:(1 ⁇ 3) by weight.
  • the API of Compound Salvia Militiorrhiza is prepared by the following crude drugs by weight parts:
  • the API of Compound Salvia Militiorrhiza is prepared by the following crude drugs by weight parts:
  • the API of Compound Salvia Militiorrhiza is prepared by the following crude drugs by weight parts:
  • the API of Compound Salvia Militiorrhiza is believed to be the active pharmaceutical ingredient of CSDP, which is prepared by extracting Salvia Militiorrhiza and Panax Notoginseng to give the extract and mixing borneol to obtain the product.
  • the preparation of the API belongs to the prior art, and the API can be prepared by the conventional methods with the crude drugs in the ratios of the present invention, or by the commercially available Salvia Militiorrhiza extract, Panax Notoginseng extract and borneol.
  • the API of Compound Salvia Militiorrhiza is preferably prepared by the following method:
  • Step (1) under an alkaline condition, Salvia Militiorrhiza and Panax Notoginseng are decocted for 1 ⁇ 3 times, 1 ⁇ 3 hours each time and the decoction is filtered to get a filtrate (Filtrate I) for later use; dregs of the decoction is further decocted with water for 1 ⁇ 3 times, 1 ⁇ 3 hours each time, the decoction is filtered to get a filtrate (Filtrate II) for later use; Filtrate I and Filtrate II are combined and concentrated to give a concentrated liquid, which is precipitated with ethanol and allows to stand still to get a supernatant; the supernatant is filtered, ethanol therein is recovered, and further concentrated to give the Salvia Militiorrhiza and Panax Notoginseng extract.
  • the alkaline condition includes, but not limited to, one or more kinds alkali selected from the group consisting of sodium bicarbonate, sodium carbonate, disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium hydroxide, potassium hydroxide and magnesium hydroxide; a pH value of 7.5 ⁇ 9.0 is preferred, ensuring sodium danshensu (sodium DL-beta-(3,4-dihydroxyphenyl)lactate) can be extracted totally.
  • alkali selected from the group consisting of sodium bicarbonate, sodium carbonate, disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium hydroxide, potassium hydroxide and magnesium hydroxide
  • a pH value of 7.5 ⁇ 9.0 is preferred, ensuring sodium danshensu (sodium DL-beta-(3,4-dihydroxyphenyl)lactate) can be extracted totally.
  • ⁇ 100% (v/v) (most preferably 95% (v/v)) ethanol solution is added to perform ethanol-precipitation, the final content of ethanol preferably is 60 ⁇ 75% (v/v).
  • the preparation method for preparing the CSMDP comprises the following steps:
  • Material melting step charging the API of Compound Salvia Militiorrhiza and the drop pill matrix in a ratio of 1:5 ⁇ 5:1 by weight into a homogenizer, mixing homogenously at 1000 ⁇ 5000 rpm for 1 ⁇ 200 min, then melting homogenously at 3000 ⁇ 10000 rpm for 1 ⁇ 100 min; during the melting process, the temperature is kept at 60 ⁇ 100° C. to obtain a molten medicine liquid;
  • Step (2) Dropping step: delivering the molten medicine liquid to a dripper, and acquiring medicine drops by means of vibration dropping at a vibration frequency of 50 ⁇ 300 Hz under a dropping pressure of 0.5 ⁇ 4.0 Bar, the temperature of the dripper is at 70° C. ⁇ 200° C.; the dropping rate is matched with the melting rate in Step (1); and,
  • Step (2) and Step (3) the pill weight is decreased from 23.5 ⁇ 27.5 mg of the traditional drop pill to 3 ⁇ 4 mg, which can be loaded into capsules; in addition, the problem of residual coolant such as liquid paraffin in the current drop pill product can be solved by using gas cooling.
  • CSMDP of the present invention was prepared by the method of Preparative Example 1 of CSMDP.
  • CSDP used as a comparative drug, was commercially available in China, prepared by Tianjin Tasly Pharmaceutical Co., Ltd.
  • Chloral hydrate and triphenyl tetrazolium chloride (TTC) were used for anesthesia.
  • Apparatus MedLab-U/8c bio-signals collecting-processing system, purchased from Nanjin Meiyi Inc.
  • Grouping the rats were randomly divided into groups according to their body weight: S group (Sham operation group), M group (Model group), Y group (Positive control group, metoprolol tartrate, Lot No. 1201039), F group (CSMDP of the present invention) and G group (CSDP available in China, Lot No. 2011L16); 10 rats in each group.
  • the animals were administrated intragastrically for 7 days, which was shown in Table 3.
  • Chest on the left front chest lateral side was incised to cut the 3 rd rib and the pericardium was carefully lifted with forceps to tear apart.
  • LAD left anterior decending branch
  • Medical suture (4-0) was used to transfix LAD and a small amount of myocardial tissue at a distance of about 1 ⁇ 2 mm from the lower edge of the left atrial appendage and inside interventricular sulcus in the vicinity of the left main trunk of coronary vein.
  • Chest was closed layer by layer. The tracheal tube was removed until the voluntary respiration was recovered in the rats. ECG was recorded continuously for 4 hours. Rats were anesthetized, their heart were cut out, sliced and dyed to calculate myocardial infarction rate (MIR). The serum was collected for later use.
  • MIR myocardial infarction rate
  • MIR (%) wet weight of the infarction region/wet weight of the whole heart ⁇ 100%
  • the descending order of the heart rate was F group, G group, M group, Y group and S group within the observation period and 0 ⁇ 1 hour after ligation. 1 hour later, the heart rate in each group was decreased. Within the observation period, the variation of heart rate in Y group and S group was relatively stable. There was no significant difference among these groups in heart rate of the rats.
  • the medicines in each group were proven to have a certain effect against myocardial infarction in the rats with a coronary artery ligature; especially the CSMDP of the present invention at a dosage of 84 mg/kg had a MIR of 3.38 ⁇ 0.49%, having a similar efficacy of MIR (3.32 ⁇ 0.59%) of the CSDP product commercially available in China at a dosage of 115 mg/kg.
  • the CSMDP at a dosage of 84 mg/kg reached the same effect with the CSDP product commercially available in China at a dosage of 115 mg/kg.
  • the CSMDP had a better efficacy than the current CSDP, having the merits such as high bioavailability, reduced administration dosage and good compliance to the patients, etc.
  • the following materials were prepared: 75 g of Salvia Militiorrhiza and Panax Notoginseng extract, 7.5 g of borneol and 165 g of PEG-6000.
  • Pre-mixing step the API of Compound Salvia Militiorrhiza was added with water to pre-mix, stirred in a heat-insulated tank at 40 ⁇ 10° C. for 60 min or longer to make the water content of the API of Compound Salvia Militiorrhiza at 13.0 wt % to give a pre-mixed material of the API of Compound Salvia Militiorrhiza for later use;
  • Step (3) Dropping step: the aforesaid molten medicine liquid was delivered to a dripper, the vibration frequency of the dripper was adjusted to 137 Hz and the temperature of the dripper was adjusted to 80° C.; the medicine liquid was flowed under pressure (1.8 Bar) into the dripper, from the bottom of which the medicine liquid was dropped down by means of vibration; the dropping rate was matched with the melting rate in Step (1);
  • Drying step the resultant drop pills were dried in a fluidized state; until the drop pills reached a better fluidized state in the bed of the fluidized bed, the temperature was increased to 25° C. to dry for 60 min, further increased to 45° C. to dry for 30 min, continuously increased to 55° C. to dry for 30 min, and decreased 30° C. or lower to discharge the drop pills.
  • the water content of the drop pills was controlled in the range of 3.0 ⁇ 7.0 wt % to give uncoated drop pills as the intermediate product;
  • Coating step the amount of coating powder was calculated based on the coating feed capacity and formulation; Opadry, which has 4 wt % of the weight of the uncoated drop pills, was used to prepare a 18 wt % coating solution and stirred for 45 min; the inlet air temperature was initially set to 25° C.; after the qualified uncoated drop pills were loaded into the fluidized bed, the inlet air temperature was increased to 48° C.; until the temperature of the materials was up to 38° C., the coating was started; the temperature of the material was kept at 35 ⁇ 45° C. during the coating and decreased 30° C.
  • the drop pills were discharged, screened to give coated drop pills as the intermediate product, the coating weigh of the coated drop pills was controlled in a range of 3.3 ⁇ 0.7 wt % and the water content was controlled in a range of 3.0 ⁇ 7.0 wt %;
  • the formation of the drop pills was measured visually by using a stroboscopic illumination to perform a real-time monitoring and adjustment.
  • the steps of screening and regulating the drop pills could be added.
  • API of Compound Salvia Militiorrhiza was prepared by the following method:
  • Step (1) under an alkaline condition (pH 8.0), Salvia Militiorrhiza and Panax Notoginseng were decocted for 2 times, 2 hours each time and filtered to give Filtrate I for later use; dregs of the decoction was further decocted with water for 2 times, 2 hours each time, filtered to give Filtrate II for later use; Filtrate I and Filtrate II were combined and concentrated to give a concentrated liquid, which was added with ethanol to make the final content of ethanol as 70% (v/v) and allowed to stand still to give a supernatant; the supernatant was taken, filtered, ethanol therein was recovered, concentrated and dried to give the Salvia Militiorrhiza and Panax Notoginseng extract.
  • an alkaline condition pH 8.0
  • the CSMDP was prepared by the same method as CSMDP PREPARATIVE EXAMPLE 1.
  • the CSMDP was prepared by the same method as CSMDP PREPARATIVE EXAMPLE 1.
  • CSMDP was prepared by the following steps:
  • Material melting step the mixture of cyclodextrin and agar (1:1) was used as a matrix, charged into a homogenizer with the API of Compound Salvia Militiorrhiza to homogenize at 1000 rpm for 1 min to give a material; the material was molten homogenously at 3000 rpm for 1 min; during the melting process, the temperature of the material was kept at 60° C. to obtain a molten medicine liquid;
  • Step (2) Dropping step: the molten medicine liquid was delivered to a dripper and dropped by means of vibration dropping at the dripper temperature of 70° C. and a vibration frequency of 50 Hz under a dropping pressure of 0.5 Bar; the dropping rate was matched with the melting rate in Step (1); and,
  • CSMDP was prepared by the following steps:
  • Material melting step the mixture of arabic gum and lactose (1:1) was used as a matrix, charged into a homogenizer with the API of Compound Salvia Militiorrhiza to homogenize at 5000 rpm for 200 min to give a material; the material was molten homogenously at 10000 rpm for 100 min; during the melting process, the temperature of the material was kept at 100° C. to obtain a molten medicine liquid;
  • Step (2) the molten medicine liquid was delivered to a dripper and dropped by means of vibration dropping at the dripper temperature of 300° C. and a vibration frequency of 300 Hz under a dropping pressure of 4.0 Bar; the dropping rate was matched with the melting rate in Step (1); and,
  • CSMDP was prepared by the following steps:
  • Material melting step the lactitol was used as a matrix, charged into a homogenizer with the API of Compound Salvia Militiorrhiza to homogenize at 2500 rpm for 100 min to give a material; the material was molten homogenously at 6000 rpm for 50 min; during the melting process, the temperature of the material was kept at 80° C. to obtain the molten medicine liquid;
  • Step (2) Dropping step: the molten medicine liquid was delivered to a dripper and dropped by means of vibration dropping at the dripper temperature of 150° C. and a vibration frequency of 150 Hz under a dropping pressure of 2 Bar; the dropping rate was matched with the melting rate in Step (1);
  • Coating step the resultant dried uncoated drop pills were coated at 40° C. in fluidized bed to obtain coated drop pills; the ratio of the coating material to the uncoated drop pills was 1:25 by weight; the concentration of the coating solution was 10 wt % and the coating material was Opadry.
  • CSMDP was prepared by the following steps:
  • API powder of Compound Salvia Militiorrhiza was added with water and stirred at 60° C. for 10 min or longer to obtain a pre-mixed API of Compound Salvia Militiorrhiza.
  • Material melting step the PEG-8000 and the pre-mixed API of Compound Salvia Militiorrhiza were charged into a homogenizer to homogenize at 2500 rpm for 100 min to give a material; the material was molten homogenously at 6000 rpm for 50 min; during the melting process, the temperature of the material was kept at 80° C. to obtain a molten medicine liquid;
  • Step (2) the molten medicine liquid was delivered to a dripper and dropped by means of vibration dropping at a dripper temperature of 150° C. and a vibration frequency of 150 Hz under a dropping pressure of 2 Bar; the dropping rate was matched with the melting rate in Step (1);
  • Coating step the resultant dried uncoated drop pills were coated at 40° C. in fluidized bed to obtain coated drop pills; the ratio of the coating material to the dried uncoated drop pills was 1:25 by weight; the concentration of the coating solution was 10 wt % and the coating material was shellac.
  • CSMDP was prepared by the following steps:
  • API powder of Compound Salvia Militiorrhiza was added with water and stirred at 30° C. for 10 min or longer to obtain a pre-mixed API of Compound Salvia Militiorrhiza.
  • Material melting step the PEG-1000 and the pre-mixed API of Compound Salvia Militiorrhiza were charged into a homogenizer to homogenize at 2500 rpm for 100 min to give a material; the material was molten homogenously at 6000 rpm for 20 min; during the melting process, the temperature of the material was kept at 100° C. to obtain a molten medicine liquid;
  • Step (2) the molten medicine liquid was delivered to a dripper and dropped by means of vibration dropping at a dripper temperature of 70° C. and a vibration frequency of 100 Hz under a dropping pressure of 1.0 Bar and an acceleration speed of 1G and a dropping rate of 10 Kg/h; the dropping rate was matched with the melting rate in Step (1);
  • the resultant drop pills were dried by a gradient-rising temperature drying method, fluidized at ⁇ 20° C., dried at 15° C. for 10 min, further dried at 35° C. for 10 min, and further dried at 55° C. for 30 min to give dried uncoated drop pills; and,
  • Coating step the resultant dried uncoated drop pills were coated at 40° C. in a fluidized bed to obtain coated drop pills; the ratio of the coating material to the dried uncoated drop pills was 1:25 by weight; the concentration of the coating solution was 10 wt % and the coating material was cellulose acetate phthalate (CAP).
  • CAP cellulose acetate phthalate
  • CSMDP was prepared by the following steps:
  • API powder of Compound Salvia Militiorrhiza was added with water and stirred at 80° C. for 10 min or longer to obtain a pre-mixed API of Compound Salvia Militiorrhiza.
  • Material melting step the mixture of PEG-4000: PEG-6000 (1:1) and the pre-mixed API of Compound Salvia Militiorrhiza were charged into a homogenizer to homogenize at 2500 rpm for 100 min to give a material; the material was molten homogenously at 6000 rpm for 80 min; during the melting process, the temperature of the material was kept at 80° C. to obtain a molten medicine liquid;
  • Step (2) the molten medicine liquid was delivered to a dripper and dropped by means of vibration dropping at a dripper temperature of 100° C. and a vibration frequency of 200 Hz under a dropping pressure of 3.0 Bar and a acceleration speed of 20G and a dropping rate of 40 Kg/h; the dropping rate was matched with the melting rate in Step (1);
  • the resultant drop pills were dried by a gradient-rising temperature drying method, fluidized at 30° C., dried at 35° C. for 120 min, at 55° C. for 60 min and at 100° C. for 60 min to give dried uncoated drop pills; and,
  • Coating step the resultant dried uncoated drop pills were coated at 35° C. in a fluidized bed to obtain coated drop pills; the ratio of the coating material to the dried uncoated drop pills was 1:25 by weight; the concentration of the coating solution was 10 wt % and the coating material was methyl acrylate.
  • CSMDP was prepared by the following steps:
  • Material melting step the xylitol was firstly charged into a melting tank and heated to 90° C. to pre-melt, into which the API of Compound Salvia Militiorrhiza was charged and well mixed to give a molten medicine liquid;
  • Drying & coating step the resultant solid drop pills were dried in a fluidized state and drug-loading coated to give coated micro drop pills with a particle size of 0.2 mm ⁇ 1.0 mm; the drying temperature was 75° C.; and,
  • Packaging step the coated micro drop pills with a particle size of 0.2 mm ⁇ 1.0 mm were loaded into capsules; 100% of the capsules were on-line checkweighed with a capsule checkweigher and packaged to give the final product.
  • the formation of drop pills was measured visually by using a stroboscopic illumination to perform real-time monitoring and adjustment.
  • the steps of screening and regulating the drop pills could be added.
  • CSMDP was prepared by the following steps:
  • Material melting step the mixture of PEG-6000 and PEG-4000 was firstly charged into a melting tank and pre-molten by heating to 120° C., into which the API of Compound Salvia Militiorrhiza was charged and well mixed to give a molten medicine liquid;
  • Drying & coating step the resultant solid drop pills were dried in a fluidized state and drug-loading coated to give coated micro drop pills with a particle size of 0.5 mm ⁇ 1.0 mm; the drying temperature was 150° C.; and,
  • Packaging step the micro drop pills were loaded into capsules; 100% of the capsules were on-line checkweighed with a capsule checkweigher and packaged to give the final product.
  • the formation of drop pills was measured visually by using a stroboscopic illumination to perform real-time monitoring and adjustment.
  • the step of screening and regulating the drop pills could be added.
  • CSMDP was prepared by the following steps:
  • Material melting step the PEG-1000 was firstly charged into a melting tank and pre-molten by heating to 40° C., into which the API of Compound Salvia Militiorrhiza was charged and well mixed to give a molten medicine liquid;
  • Drying & coating step the resultant solid drop pills were dried in a fluidized state and drug-loading coated, fluidized at 20° C., dried at 25° C. for 60 min, further dried at 45° C. for 30 min and at 55° C. for 30 min to give the coated micro drop pill with a particle size of 3.0 mm ⁇ 4.0 mm; and,
  • Packaging step the micro drop pills were loaded into capsules; 100% of the capsules were on-line checkweighed with a capsule checkweigher and packaged to give the final product.
  • the formation of drop pills was measured visually by using a stroboscopic illumination to perform real-time monitoring and adjustment.
  • the step of screening and regulating the drop pills could be added.
  • CSMDP was prepared by the following steps:
  • Material melting step the mixture of PEG-6000 and PEG-4000 was firstly charged into a melting tank and pre-molten by heating to 120° C., into which the API of Compound Salvia Militiorrhiza was charged into a homogenizer to homogenize at 1000 rpm for 1 min and molten homogenously at 3000 rpm for 1 min, during the melting process, the temperature of the material was kept at 60° C. to obtain a molten medicine liquid;
  • Drying & coating step the resultant solid drop pills were dried in a fluidized state and drug-loading coated to give coated micro drop pills with a particle size of 0.2 mm; the drying temperature was 150° C.; and,
  • Packaging step the micro drop pills were loaded into capsules; 100% of the capsules were on-line checkweighed with a capsule checkweigher and packaged to give the final product.
  • CSMDP was prepared by the following steps:
  • Material melting step the PEG-6000 was firstly charged into a melting tank and pre-molten by heating to 120° C., into which the API of Compound Salvia Militiorrhiza was charged into a homogenizer to homogenize at 5000 rpm for 200 min and molten homogenously at 10000 rpm for 1 min, during the melting process, the temperature of the material was kept at 100° C. to obtain a molten medicine liquid;
  • Drying & coating step the resultant solid drop pills were dried in a fluidized state and drug-loading coated to give coated micro drop pills with a particle size of 4.0 mm; the drying temperature was 150° C.; and,
  • Packaging step the micro drop pills were loaded into capsules; 100% of the capsules were on-line checkweighed with a capsule checkweigher and packaged to give the final product.
  • CSMDP was prepared by the following steps:
  • Material melting step the PEG-4000 was firstly charged into a melting tank and pre-molten by heating to 120° C., into which the API of Compound Salvia Militiorrhiza was charged, homogenized at 3000 rpm for 10 min and molten homogenously at 4000 rpm for 5 min, during the melting process, the temperature of the material was kept at 70 ⁇ 90° C. to obtain a molten medicine liquid;
  • CSMDP was prepared by the following steps:
  • Material melting step the PEG-4000 was firstly charged into a melting tank and pre-molten by heating to 120° C., into which the API of Compound Salvia Militiorrhiza was charged, homogenized at 4000 rpm for 60 min and molten homogenously at 9000 rpm for 30 min, during the melting process, the temperature of the material was kept at 90° C. to obtain a molten medicine liquid;
  • CSMDP was prepared by the following steps:
  • Material melting step the PEG-6000 was firstly charged into a melting tank and pre-molten by heating to 90° C., into which the API of Compound Salvia Militiorrhiza was charged and well mixed to give a molten medicine liquid;
  • Drying & coating step the resultant solid drop pills were dried in a fluidized state and drug-loading coated to give coated micro drop pills with a particle size of 1.0 mm ⁇ 2.0 mm; the drying temperature was 75° C.; and,
  • Packaging step the coated micro drop pills were loaded into capsules; 100% of the capsules were on-line checkweighed with a capsule checkweigher and packaged to give the final product.
  • the formation of drop pills was measured visually by using a stroboscopic illumination to perform real-time monitoring and adjustment.
  • the step of screening and regulating the drop pills could be added.
  • the CSMDP prepared by the methods disclosed in the CSMDP PREPARATIVE EXAMPLES 2 ⁇ 17 had the similar merits such as high bioavailability, reduced administration dosage and good compliance to the patients. Meanwhile, the CSMDP prepared by the methods disclosed in CSMDP PREPARATIVE EXAMPLE 2 ⁇ 17 had the same merits listed in Table 2.
  • Qishenyiqi drop pill is a TCM preparation prepared by Astragalus membranaceus, Salvia Militiorrhiza, Panax Notoginseng and volatile oil from Lignum Dalbergiae Odoriferae . It is capable of significantly improving symptoms such as myocardial injury and heart dysfunction, which has been used clinically for treating diseases of chronic heart failure, myocarditis and its sequelae, myocardial infarction recovery stage and myocardial fibrosis.
  • the current Qishenyiqi drop pill has the merits such as small dosage, convenient administration, rapid dissolution, direct absorption into blood by mucosa, high bioavailability and high efficacy with no gastrointestinal stimulation and no obvious toxic and side effects.
  • the preparation method for QMDP known in the prior art mainly comprises the following steps: firstly, the following crude drugs were prepared: Astragalus membranaceus, Salvia Militiorrhiza, Panax Notoginseng , volatile oil from Lignum Dalbergiae Odoriferae and PEG-6000; Salvia Militiorrhiza and Panax Notoginseng were decocted with water and precipitated with ethanol; the ethanol was recovered and concentrated to obtain the Salvia Militiorrhiza and Panax Notoginseng extract; Astragalus membranaceus was decocted with water and precipitated with ethanol to obtain deposit of Astragalus membranaceus; Lignum Dalbergiae Odoriferae was extracted with water to obtain volatile oil from Lignum Dalbergiae Odoriferae ; the Salvia Militiorrhiza and Panax Notoginseng extract, the deposit of Astragalus membranaceus and PEG-6000 were well mol
  • Qishenyiqi micro drop pills are prepared by the API and the drop pill matrix in a ratio of 1:5 ⁇ 5:1 by weight.
  • the API is prepared by the following crude drugs by weight parts:
  • the API is prepared by the following crude drugs by weight parts:
  • the API is prepared by the following crude drugs by weight parts:
  • the micro drop pills are prepared by the API and the drop pill matrix in a ratio of 1:3 ⁇ 3:1 by weight, most preferably 1: (1 ⁇ 3) by weight.
  • the API of Qishenyiqi micro drop pill is used as the active pharmaceutical ingredient, which is prepared by the following steps: Astragalus membranaceus, Salvia Militiorrhiza and Panax Notoginseng were extracted and followed by addition of volatile oil from Lignum Dalbergiae Odoriferae .
  • the preparation of the API belongs to the prior art, and the API can be prepared by the conventional methods with the crude drugs in the ratios of the present invention, or by the commercially available Astragalus membranaceus extract, Salvia Militiorrhiza extract, Panax Notoginseng extract and volatile oil from Lignum Dalbergiae Odoriferae .
  • the API is preferably prepared by the following method:
  • Step (1) under an alkaline condition, Salvia Militiorrhiza and Panax Notoginseng are decocted with water for 1 ⁇ 3 times, 1 ⁇ 3 hours each time to give a decoction, and the decoction was filtered to get a filtrate; the filtrate is concentrated to give a concentrated liquid, into which 70 ⁇ 100% (v/v) ethanol is added to make the final concentration of ethanol 50 ⁇ 70% (v/v) and allow to stand still to get a supernatant; the supernatant is taken, filtered, ethanol is recovered and concentrated to give the Salvia Militiorrhiza and Panax Notoginseng extract.
  • Salvia Militiorrhiza and Panax Notoginseng are decocted with water and an appropriate amount of alkali for 2 times, 2 hours each time and filtered to get a filtrate for each decoction; the filtrates are combined and concentrated to give a concentrated liquid with a relative density of 1.13 ⁇ 1.23 (80° C.), into which ethanol is added to make a final concentration of ethanol 65 ⁇ 70% (v/v) and allow to stand still for 12 hours or longer to get a supernatant; the supernatant is filtered, ethanol is recovered and concentrated to give the Salvia Militiorrhiza and Panax Notoginseng extract with a relative density of 1.30 ⁇ 1.38 (80° C.).
  • Step (2) Astragalus membranaceus is decocted with an alkaline aqueous solution for 1 ⁇ 3 times, 1 ⁇ 3 hours each time, to give a decoction; the decoction is filtered to give Filtrate I; dregs of the decoction is further decocted with water for 1 ⁇ 3 times, 1 ⁇ 3 hours each time, to give a decoction; the decoction is filtered to give Filtrate II; Filtrate I and Filtrate II are combined and concentrated to give a concentrated liquid, into which 50 ⁇ 100% (v/v) ethanol is added to perform ethanol precipitation for 1 ⁇ 3 times to make the final concentration of ethanol 60 ⁇ 80% (v/v) and allow to stand still to get a supernatant; the supernatant is filtered to give Filtrate III; Filtrate III is recovered and concentrated by ethanol to give the Astragalus membranaceus extract.
  • Step (2) Astragalus membranaceus is decocted with water and an appropriate amount of sodium bicarbonate for 2 hours to give a decoction; the decoction was filtered to give Filtrate I; dregs of the decoction is further decocted with water for 1 hour to give a decoction; the decoction is filtered to give Filtrate II; Filtrate I and Filtrate II are combined and concentrated to give a concentrated liquid with a relative density 1.05 ⁇ 1.20 (75 ⁇ 5° C.), ethanol is added into the concentrated liquid to make the final concentration of ethanol 60 ⁇ 1% (v/v) and allow to stand still for 12 hours or longer to get a supernatant, the supernatant is filtered and recovered ethanol under a reduced pressure to obtain a concentrated liquid with a relative density of 1.18 ⁇ 1.30 (60 ⁇ 5° C.), into which ethanol is added to make the final concentration of ethanol 80 ⁇ 1% (v/v) and allow to stand still for 12 hours
  • the alkaline condition is at a pH value of 7.5 ⁇ 9.0 and the alkali is, but not limited to, selected from the group consisting of sodium bicarbonate, sodium carbonate, disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium hydroxide, potassium hydroxide and magnesium hydroxide.
  • the preparation method for preparing the QMDP comprises the following steps:
  • Material melting step charging the API and the drop pill matrix in a ratio of 1:5 ⁇ 5:1 by weight into a homogenizer, mixing homogenously at 1000 ⁇ 5000 rpm for 1 ⁇ 200 min, melting homogenously at 3000 ⁇ 10000 rpm for 1 ⁇ 100 min; during the melting process, the temperature of the material is kept at 60 ⁇ 100° C. to obtain a molten medicine liquid;
  • Step (2) Dropping step: delivering the molten medicine liquid to a dripper at 70° C. ⁇ 300° C., and acquiring medicine drops by means of vibration dropping at a vibration frequency of 50 ⁇ 300 Hz under a dropping pressure of 0.5 ⁇ 4.0 Bar; the dropping rate is matched with the melting rate in Step (1);
  • Step (2) and Step (3) the pill weight decreased from 23.5 ⁇ 27.5 mg of the traditional drop pills to 3 ⁇ 5 mg, which can be loaded into capsules; the use of gas cooling can solve the problems such as residual coolant of liquid paraffin in the current drop pills.
  • the following materials were prepared: 80 g of the API of QMDP and 165 g of PEG-6000.
  • Pre-mixing step the API of QMDP was added with water to pre-mix, stirred in a heat-insulated tank at 40 ⁇ 10° C. for 60 min or longer to make the water content of API of QMDP at 13.0 wt % to give a pre-mixed API of QMDP for later use;
  • Drying step the resultant drop pills were dried in a fluidized state; until the drop pills reached a better fluidization state in the bed of the fluidized bed, the temperature was increased to 25° C. to dry for 60 min, further increased to 45° C. to dry for 30 min, continuously increased to 55° C. to dry for 30 min, and deceased 30° C. or lower to discharge to give uncoated drop pills as a intermediate product, and the water content of the uncoated drop pills was controlled in a range of 3.0 ⁇ 7.0 wt %;
  • Coating step the amount of coating powder was calculated based on the coating feed capacity and formulation; Opadry, which has 4 wt % of the weight of the uncoated drop pills, was used to prepare a 18 wt % coating solution and stirred for 45 min; the inlet air temperature was initially set to 25° C.; after the qualified uncoated drop pills were loaded into the fluidized bed, the inlet air temperature was increased to 48° C.; until the temperature of the drop pills was up to 38° C., the coating was started; the temperature of the material was kept in the range of 35 ⁇ 45° C. during the coating and decreased 30° C.
  • the drop pills were discharged, screened to give coated drop pills as a intermediate product, the coating weigh of the coated drop pills was controlled in a range of 3.3 ⁇ 0.7% and the water content was controlled in a range of 3.0 ⁇ 7.0 wt %; and,
  • the formation of the drop pills was measured visually by using a stroboscopic illumination to perform a real-time monitoring and adjustment.
  • the steps of screening and regulating the drop pills could be added.
  • API of QMDP was prepared by the following method:
  • Step (1) Salvia Militiorrhiza and Panax Notoginseng were decocted with water and an appropriate amount of alkali for 2 times, 2 hours each time to give a decoction, and the decoction was filtered to get filtrates; the filtrates were combined and concentrated to give a concentrated liquid with a relative density of 1.13 ⁇ 1.23 (80° C.); ethanol was added into the concentrated liquid to make a final concentration of ethanol 65 ⁇ 70% (v/v) and allowed to stand still for 12 hours or longer to get a supernatant; the supernatant was filtered, and the ethanol therein was recovered and concentrated to give the Salvia Militiorrhiza and Panax Notoginseng extract with a relative density of 1.30 ⁇ 1.38 (80° C.).
  • Step (2) Astragalus membranaceus is decocted with water and an appropriate amount of sodium bicarbonate for 2 hours to give a decoction; the decoction was filtered to give Filtrate I; dregs of the decoction is further decocted with water for 1 hour to give a decoction; the decoction is filtered to give Filtrate II; Filtrate I and Filtrate II are combined and concentrated to give a concentrated liquid with a relative density 1.05 ⁇ 1.20 (75 ⁇ 5° C.), ethanol is added into the concentrated liquid to make the final concentration of ethanol 60 ⁇ 1% (v/v) and allow to stand still for 12 hours or longer to get a supernatant, the supernatant is filtered and recovered ethanol under a reduced pressure to obtain a concentrated liquid with a relative density of 1.18 ⁇ 1.30 (60 ⁇ 5° C.), into which ethanol is added to make the final concentration of ethanol 80 ⁇ 1% (v/v) and allow to stand still for 12 hours or
  • the following materials were prepared: 100 g of Salvia Militiorrhiza and Panax Notoginseng extract, 200 g of Astragalus membranaceus extract, 10 g of volatile oil from Lignum Dalbergiae Odoriferae and 900 g of PEG-6000 as the drop pill matrix.
  • Material melting step the PEG-6000 was loaded into a melting tank and pre-molten by heating to 70 ⁇ 80° C., into which a uniform mixture of the Salvia Militiorrhiza and Panax Notoginseng extract and the Astragalus membranaceus extract as well as volatile oil from Lignum Dalbergiae Odoriferae were added, mixed and homogenized to give a molten medicine liquid;
  • Step (2) Dropping step: the molten medicine liquid was delivered to a dripper and dropped by means of vibration dropping at a dripper temperature of 80° C. and a vibration frequency of 50 Hz; the dropping rate was matched with the melting rate in Step (1); and,
  • Drying & coating step the resultant drop pills was dried in a fluidized state and drug-loading coated at 150° C., screened, regulated and packaged to obtain the final product.
  • the API of QMDP was prepared by the following crude drugs by weight parts: Astragalus membranaceus 100 parts, Salvia Militiorrhiza 50 parts, Panax Notoginseng 10 parts, volatile oil from Lignum Dalbergiae Odoriferae 0.5 parts, and the ratio of the API of QMDP to PEG-6000 was 1:5 by weight, the Qishenyiqi micro drop pills were prepared by the same method as QMDP PREPARATIVE EXAMPLE 1.
  • the API of QMDP was prepared by the following crude drugs by weight parts: Astragalus membranaceus 200 parts, Salvia Militiorrhiza 100 parts, Panax Notoginseng 20 parts, volatile oil from Lignum Dalbergiae Odoriferae 2 parts, and the ratio of the API of QMDP to PEG-6000 was 5:1 by weight, the Qishenyiqi micro drop pills were prepared by the same method as QMDP PREPARATIVE EXAMPLE 1.
  • the following materials were prepared: 80 g of the API of QMDP, 165 g of a cyclodextrin and agar (1:1) mixture.
  • the QMDP was prepared by the following method:
  • Material melting step the cyclodextrin and agar (1:1) mixture was charged into a homogenizer with the API of QMDP to homogenize at 1000 rpm for 1 min to give a material; the material was molten homogenously at 3000 rpm for 1 min; during the melting process, the temperature of the material was kept at 60° C. to obtain a molten medicine liquid;
  • Step (2) the molten medicine liquid was delivered to a dripper and dropped by means of vibration dropping at a dripper temperature of 70° C. and a vibration frequency of 50 Hz under a dropping pressure of 0.5 Bar; the dropping rate was matched with the melting rate in Step (1); and,
  • the following materials were prepared: 80 g of the API of QMDP, 165 g of arabic gum and lactose (1:1) mixture.
  • the QMDP was prepared by the following method:
  • Material melting step the arabic gum and lactose (1:1) mixture was charged into a homogenizer with the API of QMDP to homogenize at 5000 rpm for 200 min to give a material; the material was molten homogenously at 10000 rpm for 100 min; during the melting process, the temperature of the material was kept at 100° C. to obtain a molten medicine liquid;
  • Step (2) the molten medicine liquid was delivered to a dripper and dropped by means of vibration dropping at a dripper temperature of 300° C. and a vibration frequency of 300 Hz under a dropping pressure of 4.0 Bar; the dropping rate was matched with the melting rate in Step (1); and,
  • the following materials were prepared: 80 g of the API of QMDP and 165 g of lactitol.
  • the QMDP was prepared by the following method:
  • Material melting step the API of QMDP and lactitol were loaded into a homogenizer to homogenize at 2500 rpm for 100 min and molten homogenously at 6000 rpm for 50 min to give a molten medicine liquid; during the melting process, the temperature of the material was kept at 80° C.;
  • Step (2) the molten medicine liquid was delivered to a dripper and dropped by means of vibration dropping at a dripper temperature of 150° C. and a vibration frequency of 150 Hz under a dropping pressure of 2 Bar; the dropping rate was matched with the melting rate in Step (1); and,
  • Coating step the uncoated drop pills were coated at 45° C. on a fluidized bed to give coated drop pills, the ratio of the coating material of shellac to the uncoated drop pills was 1:25 by weight, the coating solution is at 10 wt %.
  • the following materials were prepared: 80 g of the API of QMDP powder and 165 g of PEG-8000.
  • the QMDP was prepared by the following method:
  • the API of QMDP powder was added with water and stirred at 60° C. for 10 min or longer to give a pre-mixed material.
  • Material melting step the pre-mixed material and PEG-8000 were loaded into a homogenizer to homogenize at 2500 rpm for 100 min and molten homogenously at 6000 rpm for 50 min to give a molten medicine liquid; during the melting process, the temperature of the material was kept at 80° C.;
  • Step (2) the molten medicine liquid was delivered to a dripper and dropped by means of vibration dropping at a dripper temperature of 150° C. and a vibration frequency of 150 Hz under a dropping pressure of 2 Bar; the dropping rate was matched with the melting rate in Step (1); and,
  • Coating step the dried uncoated drop pills were coated in a fluidized bed to coat at 35° C. to give coated drop pills; the ratio of the coating material of CAP to the uncoated drop pills was 1:25 by weight; the concentration of coating solution was 25 wt %.
  • the following materials were prepared: 90 g of the API of QMDP powder and 270 g of PEG-1000.
  • the QMDP was prepared by the following method:
  • the API of QMDP powder was added with water and stirred at 30° C. for 10 min or longer to give a pre-mixed material.
  • Material melting step the pre-mixed material and PEG-1000 were loaded into a homogenizer to homogenize at 2500 rpm for 100 min and molten homogenously at 6000 rpm for 20 min to give a molten medicine liquid; during the melting process, the temperature of the material was kept at 100° C.;
  • Step (2) the molten medicine liquid was delivered to a dripper and dropped by means of vibration dropping at a dripper temperature of 70° C., a vibration frequency of 100 Hz under a dropping pressure of 1.0 Bar, an acceleration speed of 1G and a dropping rate of 10 Kg/h, which was matched with the melting rate in Step (1);
  • the resultant drop pills were dried by a gradient-rising temperature drying method, fluidized at ⁇ 20° C., dried at 15° C. for 10 min, at 35° C. for 10 min and at 55° C. for 30 min to give dried uncoated drop pills; and,
  • Coating step the dried uncoated drop pills were coated in a fluidized bed at 40° C. to give coated drop pills; the ratio of the coating material of Opadry to the uncoated drop pill was 1:25 by weight; the concentration of coating solution was 20 wt %.
  • the following materials were prepared: 105 g of the API of QMDP powder and 35 g of a PEG-4000 and PEG-6000 (1:1) mixture.
  • the QMDP was prepared by the following method:
  • the API of QMDP powder was added with water and stirred at 80° C. for 10 min or longer to give a pre-mixed material.
  • Material melting step the pre-mixed material and the PEG-4000 and PEG-6000 (1:1) mixture were loaded into a homogenizer to homogenize at 2500 rpm for 100 min and molten homogenously at 6000 rpm for 80 min to give a molten medicine liquid; during the melting process, the temperature of the material was kept at 80° C.;
  • Step (2) the molten medicine liquid was delivered to a dripper and dropped by means of vibration dropping at a dripper temperature of 100° C., a vibration frequency of 200 Hz under a dropping pressure of 3.0 Bar, an acceleration speed of 20G and a dropping rate of 40 Kg/h, which was matched with the melting rate in Step (1);
  • the resultant drop pills were dried by a gradient-rising temperature drying method, fluidized at 30° C., dried at 35° C. for 120 min, at 55° C. for 60 min and at 100° C. for 60 min to give dried uncoated drop pills; and,
  • Coating step the dried uncoated drop pills were coated in a fluidized bed at 35° C. to give coated drop pills; the ratio of the coating material of methyl acrylate to the uncoated drop pills was 1:25 by weight; the concentration of coating solution was 5 wt %.
  • SMDP Salvia Militiorrhiza Micro Drop Pill
  • Salvia Militiorrhiza extract can either be prepared by the conventional methods or commercially available.
  • 600 g of the Salvia Militiorrhiza extract was added with water (60 g) and 600 g of PEG-6000, charged into a melting tank and totally molten and mixed to give a molten medicine liquid by heating to 90° C. ⁇ 100° C.
  • the molten medicine liquid was delivered under pressure to a dripper and dropped by means of vibration dropping at a dripper temperature of 80° C. ⁇ 100° C. and a vibration frequency of 150 Hz.
  • the drops were cooled with low-temperature nitrogen and the cooling temperature was ⁇ 140° C.
  • the drop pills were dried with a fluidized bed at 150° C. and coated with a coating solution (18 ⁇ 20 wt %), screened, regulated and packaged to give the final product.
  • Salvia Militiorrhiza extract can either be prepared by the conventional methods or commercially available.
  • the Huoxiangzhengqi extract can be prepared by the methods disclosed in Chinese patent applications CN 100563635A and CN 1745799A and patchouli oil and perilla leaf oil were commercially available.
  • Huoxiangzhengqi extract 200 g of Huoxiangzhengqi extract, 1 ml of patchouli oil, 2 ml of perilla leaf oil and 600 g of PEG-6000 were prepared. All of the Huoxiangzhengqi extract and 550 g of PEG-6000 was charged into 1# melting tank and molten by heating to 65 ⁇ 85° C. to give a uniform liquid. 1 ml of patchouli oil, 2 ml of perilla leaf oil and 50 g of PEG-6000 were charged into 2# melting tank and molten by heating to 65 ⁇ 85° C. to give a uniform liquid.
  • the liquid in 2# melting tank was delivered to the inner layer of a double-layer dripper and the liquid in 1# melting tank was delivered to the outer layer of the double-layer dripper.
  • the vibration frequency of the dripper was adjusted to 200 Hz.
  • the molten medicine liquid was flowed under pressure into the dripper and dropped by means of vibration dropping at a dripper temperature of 80° C.
  • the drops were cooled with low-temperature air to give solid drop pills.
  • the cooling temperature was ⁇ 40° C.
  • the Huoxiangzhengqi extract can be prepared by the methods disclosed in Chinese patent applications CN 100563635A and CN 1745799A and the patchouli oil and perilla leaf oil were commercially available.
  • CMC carboxymethyl cellulose
  • the CMC was charged into a melting tank and pre-molten by heating to 90 ⁇ 100° C., into which the andrographolide was added and mixed to give a uniform liquid.
  • the vibration frequency of a pneumatic dripper was adjusted to 30 Hz.
  • the temperature of the dripper was controlled at 80° C.
  • the molten medicine liquid was flowed under pressure into the dripper and dropped from the bottom of the dripper into a cooling duct.
  • the drops were cooled with low-temperature nitrogen to give solid drop pills.
  • the cooling temperature was ⁇ 20° C.
  • the drop pills were dried in a fluidized state and drug loading coated.
  • the drop pills were screened, regulated and packaged to obtain the final product with a particle size of drop pill of 1.5 mm ⁇ 2 mm.
  • the andrographolide was either prepared by the methods known in the prior art or commercially available.
  • the drop pills were dried in a fluidized state at 75° C. and drug loading coated to obtain drop pills with a particle size of 1.0 mm ⁇ 2.0 mm.
  • the drop pills were loaded into capsules, and 100% of the capsules were on-line checkweighed with a capsule checkweigher, packaged to give the final product.
  • Salvia Militiorrhiza and Ginkgo Biloba extract was prepared by the method of Chinese patent CN 1872099B.
  • the formation of drop pills was measured visually by using a stroboscopic illumination to perform real-time monitoring and adjustment.
  • the step of screening and regulating could be added.
  • the drop pills were dried in a fluidized state at 75° C. and drug loading coated to obtain drop pills with a particle size of 1.0 mm ⁇ 2.0 mm.
  • the drop pills were loaded into capsules, and 100% of the capsules were on-line checkweighed with a capsule checkweigher, packaged to give the final product.
  • Salvia Militiorrhiza and Ginkgo Biloba extract was prepared by the method of Chinese patent CN 101015527B.
  • the formation of drop pills was measured visually by using a stroboscopic illumination to perform real-time monitoring and adjustment.
  • the step of screening and regulating could be added.
  • the drops were cooled with low-temperature inert gas to give solid drop pills.
  • the cooling temperature was ⁇ 20° C.
  • the drop pills were dried in a fluidized state at 75° C. and drug loading coated to obtain drop pills with a particle size of 1.0 mm ⁇ 2.0 mm.
  • the drop pills were loaded into capsules, and 100% of the capsules were on-line checkweighed with a capsule checkweigher, packaged to give the final product.
  • the Salvia Militiorrhiza and Panax Notoginseng extract and volatile oil from Lignum Dalbergiae Odoriferae were commercially available.
  • the Salvia Militiorrhiza and Panax Notoginseng extract can be prepared by the method for preparing the Salvia Militiorrhiza and Panax Notoginseng extract in the preparation of the CSMDP or QMDP.
  • the formation of drop pills was measured visually by using a stroboscopic illumination to perform real-time monitoring and adjustment.
  • the step of screening and regulating could be added.
  • PNS Panax Notoginseng saponins
  • starch 400 g of Panax Notoginseng saponins (PNS) and 400 g of starch were prepared.
  • the starch was charged into a melting tank and pre-molten by heating to 70 ⁇ 80° C., into which the PNS was added and mixed to give a uniform liquid.
  • the vibration frequency of a pneumatic dripper was adjusted to 30 Hz.
  • the temperature of the dripper was controlled at 80° C.
  • the molten medicine liquid was flowed under pressure into the dripper that was heat-insulated by a steam jacket and dropped from the bottom of the dripper into a cooling duct.
  • the drops were cooled with low-temperature nitrogen to give solid drop pills.
  • the cooling temperature was ⁇ 20° C.
  • the drop pills were dried in a fluidized state, drug loading coated and packaged to obtain drop pills with a particle size of 0.5 mm ⁇ 1 mm.
  • micro drop pills prepared by the methods disclosed in EXAMPLES 3 ⁇ 8 had the same merits listed in Table 2.
US14/903,896 2013-07-11 2014-07-11 Formulation of a micro drop pill and the preparation method thereof Abandoned US20160151293A1 (en)

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CN201310290967.3 2013-07-11
CN201310291465.2A CN104274416B (zh) 2013-07-11 2013-07-11 一种振动滴制微滴丸的方法
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PCT/CN2014/082104 WO2015003661A1 (zh) 2013-07-11 2014-07-11 一种中药微滴丸的制备方法以及由所述方法制得的中药微滴丸

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