U.S. patent number RE49,050 [Application Number 16/713,533] was granted by the patent office on 2022-04-26 for traditional chinese medicine composition, and preparation and application thereof.
This patent grant is currently assigned to Tasly Pharmaceutical Group Co., Ltd.. The grantee listed for this patent is Tasly Pharmaceutical Group Co., Ltd.. Invention is credited to Hai'ou Dong, Lijun Fan, Naifeng Wu, Kaijing Yan, Xijun Yan, Zhengliang Ye, Shunnan Zhang, Wensheng Zhang, Yongfeng Zheng, Lihong Zhou.
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United States Patent |
RE49,050 |
Yan , et al. |
April 26, 2022 |
Traditional Chinese medicine composition, and preparation and
application thereof
Abstract
A traditional Chinese medicine composition for treating
cardiovascular disease, and a preparation thereof, particularly a
micro drop pill preparation thereof, and a method for preparing the
preparation; the method for preparing the micro drop pill
preparation can be used to prepare drop pills, coated drop pills,
and drop pill capsules with a high drug loading capacity.
Inventors: |
Yan; Xijun (Tianjin,
CN), Wu; Naifeng (Tianjin, CN), Yan;
Kaijing (Tianjin, CN), Ye; Zhengliang (Tianjin,
CN), Zhang; Shunnan (Tianjin, CN), Zhou;
Lihong (Tianjin, CN), Zhang; Wensheng (Tianjin,
CN), Dong; Hai'ou (Tianjin, CN), Zheng;
Yongfeng (Tianjin, CN), Fan; Lijun (Tianjin,
CN) |
Applicant: |
Name |
City |
State |
Country |
Type |
Tasly Pharmaceutical Group Co., Ltd. |
Tianjin |
N/A |
CN |
|
|
Assignee: |
Tasly Pharmaceutical Group Co.,
Ltd. (Tianjin, CN)
|
Family
ID: |
1000006104998 |
Appl.
No.: |
16/713,533 |
Filed: |
December 13, 2019 |
PCT
Filed: |
July 11, 2014 |
PCT No.: |
PCT/CN2014/082105 |
371(c)(1),(2),(4) Date: |
January 08, 2016 |
PCT
Pub. No.: |
WO2015/003662 |
PCT
Pub. Date: |
January 15, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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Reissue of: |
14903684 |
Jul 11, 2014 |
9987320 |
Jun 5, 2018 |
|
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Foreign Application Priority Data
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Jul 11, 2013 [CN] |
|
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201310290968.8 |
Aug 29, 2013 [CN] |
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201310384234.6 |
Jan 30, 2014 [CN] |
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201410044675.6 |
Mar 10, 2014 [CN] |
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201410085690.5 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K
31/11 (20130101); A61K 31/222 (20130101); A61K
31/216 (20130101); A61K 9/5015 (20130101); A61K
31/343 (20130101); A61K 36/537 (20130101); A61K
31/045 (20130101); A61K 9/5026 (20130101); A61K
36/258 (20130101); A61K 31/192 (20130101); A61K
9/5042 (20130101); A61K 9/5089 (20130101); A61K
31/704 (20130101); A61K 36/258 (20130101); A61K
2300/00 (20130101); A61K 36/537 (20130101); A61K
2300/00 (20130101); A61K 31/704 (20130101); A61K
2300/00 (20130101); A61K 31/192 (20130101); A61K
2300/00 (20130101); A61K 31/216 (20130101); A61K
2300/00 (20130101); A61K 31/343 (20130101); A61K
2300/00 (20130101); A61K 31/222 (20130101); A61K
2300/00 (20130101); A61K 31/11 (20130101); A61K
2300/00 (20130101); A61K 31/045 (20130101); A61K
2300/00 (20130101) |
Current International
Class: |
A61K
36/00 (20060101); A61K 31/704 (20060101); A61K
36/537 (20060101); A61K 31/045 (20060101); A61K
31/343 (20060101); A61K 36/258 (20060101); A61K
9/50 (20060101); A61K 31/11 (20060101); A61K
31/216 (20060101); A61K 31/222 (20060101); A61K
31/192 (20060101) |
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|
Primary Examiner: Campell; Bruce R
Attorney, Agent or Firm: Nixon Peabody LLP
Claims
What is claimed is:
1. A Chinese medicine composition consisting of the following
materials by weight percentage: 50.0%-99.9% of Salvia Miltiorrhiza
and Panax Notoginseng extract and 0.1%-50.0% of borneol, wherein
the Salvia Miltiorrhiza and Panax Notoginseng extract comprises the
following ingredients by weight percentage: Danshensu:Salvianolic
acid T:protocatechuic aldehyde:Salvianolic acid D:rosmarinic
acid:Salvianolic acid B:Salvianolic acid A:Panax Notoginseng
Saponin R1:Ginsenoside Rg1:Ginsenoside Re:Ginsenoside
Rb1:Ginsenoside Rd:dihydrotanshinone I:tanshinone
I:cryptotanshinone:tanshinone
IIA=(2.about.5):(0.5-1.9):(1.1-3):(0.2-1.2):(0.2-1):(0.5-2):(0.5-2):(0.2--
1):(1.5-4):(0.1-0.5):(1-3.9):(0.1-1):(0.01-0.05):(0.05-0.1):(0.02-0.1):(0.-
1-0.5).
2. The Chinese medicine composition according to claim 1, wherein
said Chinese medicine composition consists of the following
materials by weight percentage: 75.0%-99.9% of Salvia Miltiorrhiza
and Panax Notoginseng extract and 0.1%-25.0% of borneol.
3. The Chinese medicine composition according to claim 1, wherein
said Chinese medicine composition consists of the following
materials by weight percentage: 90.0%-99.9% of Salvia Miltiorrhiza
and Panax Notoginseng extract and 0.1%-10.0% of borneol.
4. The Chinese medicine composition according to claim 1, wherein
the Salvia Miltiorrhiza and Panax Notoginseng extract comprises the
following ingredients by weight parts: Danshensu:Salvianolic acid
T:protocatechuic aldehyde:Salvianolic acid D:rosmarinic
acid:Salvianolic acid B:Salvianolic acid A:Panax Notoginseng
Saponin R1:Ginsenoside Rg1:Ginsenoside Re:Ginsenoside
Rb1:Ginsenoside Rd:dihydrotanshinone I:tanshinone
I:cryptotanshinone:tanshinone
IIA=(3-5):(0.8-1.5):(1.1-2):(0.5-1):(0.4-0.9):(1-2):(0.5-1.5):(0.4-1):(1.-
5-3):(0.1-0.5):(1.3-3):(0.1-0.8):(0.02-0.05):(0.05-0.1):(0.02-0.1):(0.15-0-
.4).
5. The Chinese medicine composition according to claim 4, wherein
the Salvia Miltiorrhiza and Panax Notoginseng extract comprises the
following ingredients by weight parts: Danshensu:Salvianolic acid
T:protocatechuic aldehyde:Salvianolic acid D:rosmarinic
acid:Salvianolic acid B:Salvianolic acid A:Panax Notoginseng
Saponin R1:Ginsenoside Rg1:Ginsenoside Re:Ginsenoside
Rb1:Ginsenoside Rd:dihydrotanshinone I:tanshinone
I:cryptotanshinone:tanshinone
IIA=3.7:1.1:1.7:0.6:0.7:1.3:0.9:0.7:2.3:0.3:1.9:0.4:0.03:0.07:0.06:0.27.
6. The Chinese medicine composition according to claim 1, wherein
the Salvia Miltiorrhiza and Panax Notoginseng extract is prepared
with the following crude medicine by weight parts: Salvia
Miltiorrhiza 75.about.90 parts and Panax Notoginseng 10.about.25
parts.
7. A pharmaceutical preparation comprising the Chinese medicine
composition according to claim 1 and pharmaceutically acceptable
carriers.
8. The pharmaceutical preparation according to claim 7, wherein
said pharmaceutical preparation is in a dosage form of a drop pill
or a micro drop pill, wherein said micro drop pill is prepared with
the Chinese medicine composition and drop pill matrix in a ratio of
1:5-5:1 by weight.
9. The pharmaceutical preparation according to claim 8, wherein
said pharmaceutical preparation is a compound Salvia micro drop
pill.
10. The Chinese medicine composition according to claim 1, wherein
the Salvia Miltiorrhiza and Panax Notoginseng extract comprises the
following ingredients by weight parts: Danshensu:Salvianolic acid
T:protocatechuic aldehyde:Salvianolic acid D:rosmarinic
acid:Salvianolic acid B:Salvianolic acid A: Panax Notoginseng
Saponin R1:Ginsenoside Rg1:Ginsenoside Re:Ginsenoside
Rb1:Ginsenoside Rd:dihydrotanshinone I:tanshinone
I:cryptotanshinone:tanshinone
IIA=(3.4.about.4.2):(1.0.about.1.3):(1.5.about.1.9):(0.5.about.0.7):(0.5.-
about.0.9):(1.1.about.1.6):(0.7.about.1.2):(0.5.about.0.9):(1.9.about.2.5)-
:(0.2.about.0.4):(1.6.about.2.2):(0.2.about.0.6):(0.03.about.0.04):(0.07.a-
bout.0.08):(0.05.about.0.06):(0.26.about.0.28).
11. A preparation method for forming the micro drop pill according
to claim 9, comprising the following steps: (1) Material melting
step: charging the medicine and drop pill matrix 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 is kept at 60-100.degree. C. to
obtain the molten medicine liquid; the ratio of the medicine to the
micro drop pill matrix is 1:5-5:1 by weight; (2) Dropping step:
delivering the molten medicine liquid to a dripper, and acquiring
medicine drops from the dripper by means of vibration dropping at a
vibration frequency of 2-2000 Hz under a dropping pressure of
0.5-4.0 Bar, with an acceleration at 1-20 G; and the temperature of
the dripper is at 70-300.degree. C.; the dropping rate is matched
with the melting rate in step (1); and (3) Condensation step:
cooling the medicine drops with cooling gas rapidly to solidify and
obtaining solid drop pill having a particle size of 0.2
mm.about.4.0 mm; the temperature of the cooling gas is 0.degree. C.
or lower.
12. The preparation method according to claim 11, wherein in step
(1), said drop pill matrix includes one or more of PEG, sorbitol,
xylitol, lactitol, maltose, starch, methylcellulose, sodium
carboxymethyl cellulose, hydroxypropyl methylcellulose (HPMC),
Arabic gum, alginate, dextrin, cyclodextrin, agar and lactose.
13. The preparation method according to claim 11, wherein said
method comprises the following steps: (1) Material melting step:
charging the medicine and matrix into a homogenizer, mixing
homogenously at 1000-5000 rpm, melting homogenously at 3000-10000
rpm for 20-80 min; during the melting process, the temperature is
kept at 80-100.degree. C. to obtain the molten medicine liquid; the
ratio of the medicine to the micro drop pill matrix is 1:3-3:1 by
weight; (2) Dropping step: delivering the molten medicine liquid to
a 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, with an acceleration at 1-15 G;
the temperature of the dripper is at 70-200.degree. C.; the
dropping rate is matched with the melting rate in step (1); and (3)
Condensation step: cooling the medicine drops with cooling gas
rapidly to solidify and obtaining solid drop pill having a particle
size of 0.2 mm-4.0 mm; the temperature of the cooling gas is
0.degree. C. or lower.
14. The preparation method according to claim 11, wherein said
method additionally comprises a step (4) of drying: fluidized-bed
drying device is utilized to perform drying at -20-100.degree. C.,
for 1-4 hours to obtain a blank drop pill.
15. The preparation method according to claim .[.11.].
.Iadd.14.Iaddend., wherein said method additionally comprises step
(5) of coating: coating the blank pill obtained from step (4) in a
state of fluidization under 30-65.degree. C.; wherein the
concentration of coating liquid is at 5-25 wt %, coating material
is selected from shellac, CAP (cellulose acetate phthalate), methyl
acrylate, .Iadd.or .Iaddend.methyl methacrylate .[.or opadry.].;
the ratio of the coating material to the blank drop pill is
1:50-1:10.
16. The preparation method according to claim 11, wherein said
method additionally comprises a premixing step before step (1):
adding medicine powder or extract with water, stirring for 10 min
or longer at 30-80.degree. C. to obtain a premixed medicine
material.
17. A method for treating acute myocardial infarction and acute
myocardial ischemia, comprising administrating the Chinese medicine
composition according to claim 1 to a subject in need thereof.
18. The preparation method according to claim 13, wherein in step
(1), mixing homogeneously 3000.about.5000 rpm for 10.about.60 min
and melting homogeneously at 4000.about.9000 rpm for 5.about.30
min, during the melting process, the temperature is kept at
70.about.90.degree. C.; in step (2), the temperature of the dripper
is at 70.about.100.degree. C.; the vibration frequency is at
50.about.300 Hz; the acceleration is at 3.5.about.4.5 G; in step
(3), the cooling gas is selected from air, nitrogen and inert gas;
the temperature of the cooling gas is 0.about.-150.degree. C.
19. The preparation method according to claim 18, wherein in step
(1), the ratio of the medicine to the matrix is 1:(1.about.3) by
weight, mixing homogeneously 3000.about.4000 rpm for 10.about.30
min and melting homogeneously at 4000.about.6000 rpm for 6.about.30
min, and during the melting process, the temperature is kept at
75.about.85.degree. C., in step (2) the temperature of the dripper
is at 75.about.85.degree. C., the vibration frequency is at
100.about.200 Hz the acceleration is at 3.5.about.4.5 G, the
dropping pressure is at 1.0.about.3.0 Bar, and the dropping rate is
10.about.40 kg/h; in step (3), the cooling gas is selected from
air, nitrogen and inert gas; the temperature of the cooling gas is
-80.about.-120.degree. C.; the particle size is 1.0 mm.about.2.0
mm.
20. The preparation method according to claim 11, wherein said
method additionally comprises a step (4) of drying: gradient-rising
temperature drying method is used as follows: fluidizing at
-20.about.30.degree. C., drying at 15.about.35.degree. C. for
10.about.120 min, drying at 35.about.55.degree. C. for 10.about.60
min, drying at 55.about.100.degree. C. for 0.about.60 min.
21. The preparation method according to claim 11, wherein said
method additionally comprises a step (4) of drying: fluidizing at
0.about.20.degree. C., drying at 25.degree. C. for 60 min, drying
at 45.degree. C. for 30 min, drying at 55.degree. C. for 0.about.30
min.
.[.22. The preparation method according to claim 11, comprising the
following steps: taking 82.5 g of Chinese medicine composition and
165 g of PEG-6000, (1) Pre-mixing step: the Chinese medicine
composition is added with water to pre-mix, stirred in the soaking
tank at 40.+-.10.degree. C. over 60 min to make the water content
of the composition at 13.0 wt % to give the pre-mixed material for
later use; (2) Melting step: PEG-6000 is firstly input into the
melting tank, pre-molten by heating to 90.degree. C., into which
the pre-mixed material is added and the resultant liquid is mixed
by low-speed homogenization (3200 rpm); after mixing, the
homogenization rate is increased to 5000 rpm to melt for 6 min;
during the melting process, temperature of the liquid is kept at
80.+-.5.degree. C. to give the molten medicine liquid; (3) Dropping
step: said molten medicine liquid is delivered to the dripper, the
vibration frequency of dripper adjusted to 137 Hz and temperature
of dripper adjusted to 80.degree. C.; the liquid is delivered to
the dripper under pressure (1.8 Bar), from which the liquid is
dropped down by means of vibration; said dropping rate is matched
with the melting rate in step (1); and (4) Condensation step: the
drops are cooled in cooling duct with the low-temperature inert gas
at -115.+-.5.degree. C. to cool the liquid to form the solid drop
pill; (5) Drying step: resultant drop pill is fluidization dried;
until the drop pill reached better fluidization state, the
temperature is increased to 25.degree. C. to dry for 60 min,
continuously increased to 55.degree. C. to dry for 30 min, and
deceased to 30.degree. C. or lower to discharge to give the
intermediate blank drop pill with the water content controlled in
the range of 3.0.about.7.0 wt %; (6) Coating step: the amount of
coating powder is calculated based on coating feed capacity and
formula; Opadry accounting for 4 wt % of the blank drop pill is
used to prepare the 18 wt % coating solution and stirred for 45
min; inlet air temperature is initially set to 25.degree. C.; after
the standard blank drop pills are loaded into the fluidized bed,
the inlet air temperature is increased to 48.degree. C.; until the
temperature of the drop pill grew to 38.degree. C., the coating is
started; the temperature is kept in the range of
35.about.45.degree. C. during the coating and decreased to
30.degree. C. or lower after coating; the pills are discharged,
screened to get the intermediate coating the drop pills with the
coating weight of 3.3.+-.0.7% and the water content in the range of
3.0.about.7.0 wt %; (7) Loading into capsule and packaging step:
the resultant micro drop pills with the particle size of 1.0 mm-2.0
mm are loaded into the capsules; 100% of capsules are on-line
checkweighed with a capsule checkweigher, packaged to give the
final product, wherein, during the process of dropping, formation
of drop pill is measured visually by using stroboscopic
illumination to perform real-time monitoring and adjustment; and
optionally, the step of screening and regulating is added..].
.Iadd.23. The Chinese medicine composition according to claim 4,
wherein the Salvia Miltiorrhiza and Panax Notoginseng extract is
prepared with the following crude medicine by weight parts: Salvia
Miltiorrhiza 75-90 parts and Panax Notoginseng 10-25
parts..Iaddend.
.Iadd.24. A pharmaceutical preparation comprising the Chinese
medicine composition according to claim 4 and pharmaceutically
acceptable carriers..Iaddend.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is .[.an.]. .Iadd.a reissue of U.S. Pat. No.
9,987,320 issued on Jun. 5, 2018, which claims priority to
.Iaddend.U.S. national stage of PCT/CN2014/082105, filed on Jul.
11, 2014, which claims priority to Chinese Patent Application No.
201310290968.8, filed on Jul. 11, 2013; Chinese patent application
No. 201310384234.6, filed on Aug. 29, 2013; Chinese patent
application No. 201410044675.6, filed on Jan. 30, 2014; and Chinese
patent application No. 201410085690.5, filed on Mar. 10, 2014, the
contents of which are each incorporated herein by reference in its
entirety.
FIELD OF THE INVENTION
The present invention relates to a traditional Chinese medicine
composition and a preparation thereof, more particular to a
traditional Chinese medicine composition for treating
cardiovascular disease and a preparation thereof, especially a
micro drop pill preparation. Also, the present invention relates to
a method for preparing the traditional Chinese medicine and the
preparation thereof Wherein, the method for preparing the micro
drop pill preparation can be used to prepare the drop pills, coated
drop pills and drop pill capsules with high drug-loading
capacity.
BACKGROUND OF THE INVENTION
With the improvement of living standards, worldwide population
aging and younger onset population, the patients with cerebral and
cardiovascular diseases are increased year by year. It has become
the second large disease that does harm to human health. Angina
pectoris is a clinical syndrome which is characterized in chest
pain and chest discomfort, caused by myocardial temporary ischemia
and hypoxia. Coronary heart disease (CHD) angina pectoris means the
pectoris induced by myocardial ischemia and hypoxia that is caused
by coronary arteriosclerosis or spasm, accounting for about 90% of
the patients with angina pectoris.
Now, the methods for treating angina pectoris are dominated by
dilating vessels, reducing blood viscosity and inhibiting platelets
aggregation as well as anticoagulation. Traditionally, the
chemicals include the nitrate, nitrite, .beta.-receptor blocker and
calcium antagonist. However, due to the stronger toxicity and side
effect, these drugs are not suitable to use for long time. In
addition, most of them focus on symptomatic treatment with no more
effect on disease progress. Occasionally, symptoms occur after
administrating the nitroglycerin, for example the head pain, head
throbbing, speed-up heartbeat and even syncope (see New
Pharmaceutics, 14.sup.th edition, p 264). Recently, the
nitroglycerin was reported to have problems of inducing severe
hypotension (see China Journal of Modern Medicine, 1997, 7 (4): 42,
Shanxi Medicine Journal, 1996, 25(2) 315) and of being prone to
producing tolerance (see Nanfang Journal of Nursing, 1996,
3(5):7.about.9). Hence, this hindered its application in
clinic.
Although a lot of traditional Chinese medicines have been used for
treating angina pectoris, the pill, powder, ointment, Dan and
decoction had become ancient history, which is seldom used by
modern people. Now, there are common compound Salvia tablet and
capsule commercially available. Because the production processes
for the tablet and capsule are outdated, the content of active
ingredients is low with no quality control indices. Both are
absorbed into blood via the gastrointestinal tract after oral
administration. Due to the hepatic first pass effect, they have low
bioavailability and slow absorption, and are not competent to the
first aid for the patients with angina pectoris.
Drop pill is a traditional preparation for traditional Chinese
medicine. It has the following merits: reduced volatility of drug,
increased drug stability, high bioavailability, quickened onset of
effect, prolonged action in topical administration, shortened
production cycle, dust pollution-free, and easily carried on.
However, the preparation method of traditional drop pill is to melt
a medicine liquid and drop it into immiscible cooling medium to
give the drop pill. Because the drop pill is formed by the factors
of downwards gravity, surface tension of medicine liquid and
internal stress, the unit drug loading capacity is small (usually,
the drug loading capacity of API is about 25%.) and the amount of
matrix very large. This does not meet the requirement of
international market that the maximum daily dose of PEG matrix
should not exceed 700 mg. Moreover, it is difficult to prepare the
traditional drop pill with diameter of less than 2.5 mm, so the
patients have to take a lot of hard-to-swallow pills each time,
which will not satisfy the fast-paced trend of modern life, and be
prone to the problems of inaccurate dose. Thus, it is generally
unacceptable by the international consumers. In addition, there are
a number of shortcomings in the preparation of traditional drop
pill, e.g. the low dropping rate, poor roundness and large
variation on the pill weight and particle size, as well as small
unit drug loading capacity and large amount of matrix (due to
sufficient medium to ensure dropping effect). Because the cooling
liquid has been used for solidifying the drop pill, the necessary
step is needed in the sequent process to remove the cooling liquid,
and the remaining cooling liquid may pose the problem of residual
organic solvent. Besides, drying methods for the traditional drop
pill have the defects of prolonged time, slow speed, uneven drying
and easily leading to evaporation of volatile oil and precipitation
of Borneol that is included in the products.
As a result of this, how to find a production process for preparing
micro drop pills, regular drop pills and drop pill capsules that
achieves high production rate, reduces amount of matrix and
increases drug-loading capacity is an important subject in need of
development and exploration of the modern formulation technique for
drop pill.
Compound Salvia Drop Pill (CSDP) is a traditional Chinese medicine
developed by Tasly Pharmaceutical Co., Ltd, which is proven to have
the effects of activating blood by removing stasis as well as
stopping pain by regulating Qi, used for treating chest distress
and angina pectoris. The main ingredients of CSDP include Salvia
Miltiorrhiza, Panax Notoginseng and Borneol. Its pharmacological
effects include increasing coronary blood flow, protecting ischemia
myocardium by strengthening hypoxia tolerance, anti-platelet
aggregation, preventing thrombosis and improving microcirculation
etc. Although the preparation of CSDP is known as a very mature
technique in the prior art, there are still a lot of problems faced
during preparation process, e.g. large amount of matrix and small
drug-loading capacity.
CONTENT OF THE INVENTION
The objective of present invention is to provide a traditional
Chinese medicine composition for treating acute myocardial
infarction and acute myocardial ischemia. Said composition is
composed of following materials by weight percentage: 50.0%-99.9%
of Salvia Miltiorrhiza and Panax Notoginseng extract and 0.1%-50.0%
of Borneol. Wherein, the Salvia Miltiorrhiza and Panax Notoginseng
extract comprises following ingredients by weight parts:
Danshensu:Salvianolic acid T:protocatechuic aldehyde:Salvianolic
acid D:rosmarinic acid:Salvianolic acid B:Salvianolic acid A:Panax
Notoginseng Saponin R1:Ginsenoside Rg1:Ginsenoside Re:Ginsenoside
Rb1:Ginsenoside Rd:dihydrotanshinone I:tanshinone
I:cryptotanshinone:tanshinone
IIA=(2.about.5):(0.5.about.1.9):(1.1.about.3):(0.2.about.1.2):(0.2.about.-
1):(0.5.about.2):(0.5.about.2):(0.2.about.1):(1.5.about.4):(0.1.about.0.5)-
:(1.about.3.9):(0.1.about.1):(0.01.about.0.05):(0.05.about.0.1):(0.02.abou-
t.0.1):(0.1.about.0.5).
In an embodiment of this invention, said composition may be
prepared into various kinds of preparations, such as injections,
tablets, capsules, drop pills and micro drop pills, preferably the
micro drop pill. Said micro drop pill means a smaller-sized drop
pill than the traditional drop pill. In particular, said micro drop
pill has the particle size of 0.2 mm.about.4 mm, especially 0.2
mm.about.2 mm, most preferably 1 mm.about.2 mm.
Another objective of present invention is to provide a compound
Salvia micro drop pill (CSMDP). In said micro drop pill, the weight
ratio of medicine to matrix is 1:5.about.5:1, and particle size 0.2
mm.about.4 mm. The preparation method for preparing said micro drop
pill comprises the steps as follows:
Material melting step: heating and melting medicine and a drop pill
matrix to obtain a molten medicine liquid;
Dropping step: delivering the molten medicine liquid to a dripper,
and acquiring medicine drops of the molten medicine liquid by means
of vibration dropping; and
Condensation step: cooling the medicine drops with cooling gas to
obtain micro drop pills.
In particular, the present invention comprises technical solutions
as follows:
1. A traditional Chinese medicine composition composed of the
following materials by weight percentage: 50.0%.about.99.9% of
Salvia Miltiorrhiza and Panax Notoginseng extract and
0.1%.about.50.0% of borneol, wherein the Salvia Miltiorrhiza and
Panax Notoginseng extract comprises following ingredients by weight
percentage:
Danshensu:Salvianolic acid T:protocatechuic aldehyde:Salvianolic
acid D:rosmarinic acid:Salvianolic acid B:Salvianolic acid A:Panax
Notoginseng Saponin R1:Ginsenoside Rg1:Ginsenoside Re:Ginsenoside
Rb1:Ginsenoside Rd:dihydrotanshinone I:tanshinone
I:cryptotanshinone:tanshinone
IIA=(2.about.5):(0.5.about.1.9):(1.1.about.3):(0.2.about.1.2):(0.2.about.-
1):(0.5.about.2):(0.5.about.2):(0.2.about.1):(1.5.about.4):(0.1.about.0.5)-
:(1.about.3.9):(0.1.about.1):(0.01.about.0.05):(0.05.about.0.1):(0.02.abou-
t.0.1):(0.1.about.0.5).
2. The traditional Chinese medicine composition according to
1.sup.st paragraph, wherein said composition is composed of
following materials by weight percentage: 75.0%.about.99.9% of
Salvia Miltiorrhiza and Panax Notoginseng extract and
0.1%.about.25.0% of bomeol.
3. The traditional Chinese medicine composition according to
1.sup.st paragraph, wherein said composition is composed of the
following materials by weight percentage: 90.0%.about.99.9% of
Salvia Miltiorrhiza and Panax Notoginseng extract and
0.1%.about.10.0% of borneol.
4. The traditional Chinese medicine composition according to any
one of 1.sup.st.about.3.sup.rd paragraphs, wherein the Salvia
Miltiorrhiza and Panax Notoginseng extract comprises following
ingredients by weight parts:
Danshensu:Salvianolic acid T:protocatechuic aldehyde:Salvianolic
acid D:rosmarinic acid:Salvianolic acid B:Salvianolic acid A:Panax
Notoginseng Saponin R1:Ginsenoside Rg1:Ginsenoside Re:Ginsenoside
Rb1:Ginsenoside Rd:dihydrotanshinone I:tanshinone
I:cryptotanshinone:tanshinone
IIA=(3.1.about.4.2):(1.0.about.1.3):(1.5.about.1.9):(0.5.about.0.7):(0.5.-
about.0.9):(1.1.about.1.6):(0.7.about.1.2):(0.5.about.0.9):(1.9.about.2.5)-
:(0.2.about.0.4):(1.6.about.2.2):(0.2.about.0.6):(0.03.about.0.04):(0.07.a-
bout.0.08):(0.05.about.0.06):(0.26.about.0.28).
5. The traditional Chinese medicine composition according to
4.sup.th paragraph, wherein the Salvia Miltiorrhiza and Panax
Notoginseng extract comprises following ingredients by weight
parts:
Danshensu:Salvianolic acid T:protocatechuic aldehyde:Salvianolic
acid D:rosmarinic acid:Salvianolic acid B:Salvianolic acid A:Panax
Notoginseng Saponin R1:Ginsenoside Rg1:Ginsenoside Re:Ginsenoside
Rb1:Ginsenoside Rd:dihydrotanshinone I:tanshinone
I:cryptotanshinone:tanshinone
IIA=3.7:1.1:1.7:0.6:0.7:1.3:0.9:0.7:2.3:0.3:1.9:0.4:0.03:0.07:0.06:0.27.
6. The traditional Chinese medicine composition according to any
one of paragraphs, wherein the Salvia Miltiorrhiza and Panax
Notoginseng extract is prepared with following crude medicine by
weight parts: Salvia Miltiorrhiza 75.about.90 parts and Panax
Notoginseng 10.about.25 parts.
7. The traditional Chinese medicine composition according to
6.sup.th paragraph, wherein the Salvia Miltiorrhiza and Panax
Notoginseng extract is prepared with following crude medicine by
weight parts: Salvia Miltiorrhiza 82.about.84 parts, Panax
Notoginseng 16.about.17 parts.
8. A pharmaceutical preparation comprising the traditional Chinese
medicine composition according to any one of
1.sup.st.about.7.sup.th paragraphs and pharmaceutically acceptable
carriers.
9. The pharmaceutical preparation according to 8.sup.th paragraph,
wherein said preparation is in a dosage form of drop pill or micro
drop pill, preferably the micro drop pill, wherein said micro drop
pill is prepared with the traditional Chinese medicine composition
and the drop pill matrix in a ratio of 1:5.about.5:1 by weight.
10. A compound Salvia micro drop pill, wherein said micro drop pill
is prepared with the traditional Chinese medicine composition
according to any one of 1.sup.st.about.7.sup.th paragraphs and drop
pill matrix in a ratio of 1:5.about.5:1 by weight.
11. The preparation method for the micro drop pill according to
10.sup.th paragraph, comprising following steps: (1) Material
melting step: charging said medicine and matrix into a homogenizer,
mixing homogenously at 1000.about.5000 rpm for 1.about.200 min,
melting homogenously at 3000.about.10000 rpm for 1.about.100 min;
during the melting process, the temperature is kept at
60.about.100.degree. C. to obtain the molten medicine liquid; said
ratio of medicine to the micro drop pill matrix is 1:5.about.5:1 by
weight; (2) Dropping step: delivering the molten medicine liquid to
a dripper, and acquiring medicine drops from the dripper by means
of vibration dropping at a vibration frequency of 2.about.2000 Hz
under a dropping pressure of 0.5.about.4.0 Bar, with an
acceleration at 1.about.20 G; the temperature of the dripper is at
70.about.300.degree. C.; the dropping rate is matched with the
melting rate in step (1); and (3) Condensation step: cooling the
medicine drops with cooling gas rapidly to solidify and obtaining
the solid drop pill having a particle size of 0.2 mm.about.4.0 mm;
the temperature of the cooling gas is 0.degree. C. or lower.
12. The preparation method according to 11.sup.th paragraph,
wherein in step (1), said drop pill matrix includes one or more of
PEG, sorbitol, xylitol, lactitol, maltose, starch, methylcellulose,
sodium carboxymethyl cellulose, hydroxypropyl methylcellulose
(HPMC), Arabic gum, alginate, dextrin, cyclodextrin, agar and
lactose, preferably the solid PEG, e.g. PEG-1000, PEG-2000,
PEG-3000, PEG-4000, PEG-5000, PEG-6000, PEG-7000 and PEG-8000, more
preferably one or more of the PEG-1000, PEG-2000, PEG-3000,
PEG-4000, PEG-6000, PEG-8000, most preferably the PEG-6000,
PEG-4000, or the combination of PEG-4000 and PEG-6000.
13. The preparation method according to 11.sup.th or 12.sup.th
paragraph, wherein said method comprises the following steps: (1)
Material melting step: charging the medicine and matrix into a
homogenizer, mixing homogenously at 1000.about.5000 rpm, melting
homogenously at 3000.about.10000 rpm for 20.about.80 min; during
the melting process, the temperature is kept at
80.about.100.degree. C. to obtain the molten medicine liquid; the
ratio of the medicine to the micro drop pill matrix is
1:3.about.3:1 by weight; (2) Dropping step: delivering the molten
medicine liquid to a dripper, and acquiring medicine drops from the
dripper by means of vibration dropping at a vibration frequency of
20.about.300 Hz under a dropping pressure of 0.5.about.4.0 Bar,
with an acceleration at 1.about.15 G; the temperature of the
dripper is at 70200.degree. C.; the dropping rate is matched with
the melting rate in step (1); and (3) Condensation step: cooling
the medicine drops with cooling gas rapidly to solidify and
obtaining solid drop pill having a particle size of 0.2
mm.about.4.0 mm; the temperature of the cooling gas is 0.degree. C.
or lower.
14. The preparation method according to 12.sup.th paragraph,
wherein in step (1), the ratio of the medicine to the drop pill
matrix is 1:3.about.3:1 by weight, mixing homogeneously
3000.about.5000 rpm for 10.about.60 min and melting homogeneously
at 4000.about.9000 rpm for 5.about.30 min, during the melting
process, the temperature is kept at 70.about.90.degree. C.;
preferably, the ratio of the medicine to the matrix is
1:(1.about.3) by weight, mixing homogeneously 3000.about.4000 rpm
for 10.about.30 min and melting homogeneously at 4000.about.6000
rpm for 6.about.30 min, and during the melting process the
temperature is kept at 75.about.85.degree. C.
15. The preparation method according to 12.sup.th paragraph,
wherein in step (2), the temperature of the dripper is at
70.about.100.degree. C., preferably at 75.about.85.degree. C.; the
vibration frequency is at 50.about.300 Hz, preferably at
100.about.200 Hz, more preferably at 90.about.200 Hz, more
preferably at 130.about.140 Hz, most preferably at 137 Hz; the
acceleration is at 3.5.about.4.5 G, preferably at 4.0 G; the
dropping pressure is at 1.0.about.3.0 Bar, preferably at 1.8 Bar;
and the dropping rate is 10.about.40 kg/h, preferably 12.about.30
kg/h, further preferably 15.about.25 kg/h.
16. The preparation according to 12.sup.th paragraph, wherein in
step (3), the cooling gas is selected from air, nitrogen and inert
gas; the temperature of the cooling gas is 0.about.150.degree. C.,
preferably -60.about.140.degree. C., more preferably
-80.about.120.degree. C.; the particle size is 1.0 mm.about.2.0
mm.
17. The preparation method according to any one of
11.sup.th.about.16.sup.th paragraphs, wherein said method may
additionally comprise step (4) of drying: fluidized-bed drying to
perform drying at --20.about.100.degree. C., preferably
-20.about.90.degree. C., for 1.about.4 hours to obtain a blank drop
pill.
18. The preparation method according to 17.sup.th paragraph,
wherein a low-temperature drop pill from step (3) is dried with
fluidized bed at 40.about.150.degree. C., preferably
40.about.60.degree. C. for 1.about.4 hours, preferably 1.about.3
hours, most preferably 2 hours, to obtain the blank pill.
19. The preparation method according to 18.sup.th paragraph,
wherein in step (4), gradient-rising temperature drying method is
used as follows: fluidizing at -20.about.30.degree. C., drying at
15.about.35.degree. C. for 10.about.120 min, drying at
35.about.55.degree. C. for 10.about.60 min, drying at
55.about.100.degree. C. for 0.about.60 min; preferably fluidizing
at 0.about.20.degree. C., drying at 25.degree. C. for 60 min,
drying at 45.degree. C. for 30 min, drying at 55.degree. C. for
0.about.30 min.
20. The preparation method according to any one of
11.sup.th.about.19 paragraphs, wherein said method may additionally
comprise step (5) of coating: coating the blank pill obtained from
step (4) in a state of fluidization under 30.about.65.degree. C.;
wherein the concentration of coating liquid is at 5.about.25 wt %,
preferably 18.about.20 wt %; coating material is selected from
shellac, CAP (cellulose acetate phthalate), methyl acrylate, methyl
methacrylate or opadry; the ratio of the coating material to the
blank drop pill is 1:50.about.1:10, preferably 1:50.about.1:25.
21. The preparation method according to any one of
11.sup.th.about.20.sup.th paragraphs, wherein said method may
additionally comprise a premixing step before step (1): adding
medicine powder or extract with water, stirring for 10 min or
longer at 30.about.80.degree. C. to obtain a premixed medicine
material.
22. Use of the traditional Chinese medicine composition according
to 1.sup.st.about.7th paragraphs in preparation of a medicament for
treating acute myocardial infarction and acute myocardial
ischemia.
DESCRIPTION OF THE DRAWINGS
FIG. 1 was the high resolution mass spectrum of salvianolic acid T,
A: (R)-salvianolic acid T; B: (S)-salvianolic acid T.
FIG. 2 was the .sup.1H-NMR spectrum of salvianolic acid T (500 MHz,
DMSO), A: (R)-salvianolic acid T; B: (S)-salvianolic acid T.
FIG. 3 was the .sup.13C-NMR spectrum of salvianolic acid T (125
MHz, DMSO), A: (R)-salvianolic acid T; B: (S)-salvianolic acid
T.
FIG. 4 was the DEPT spectrum of salvianolic acid T, A:
(R)-salvianolic acid T; B: (S)-salvianolic acid T.
FIG. 5 was the COSY spectrum of salvianolic acid T, A:
(R)-salvianolic acid T; B: (S)-salvianolic acid T.
FIG. 6 was the ROESY spectrum of salvianolic acid T, A:
(R)-salvianolic acid T; B: (S)-salvianolic acid T.
FIG. 7 was the HSQC spectrum of salvianolic acid T, A:
(R)-salvianolic acid T; B: (S)-salvianolic acid T.
FIG. 8 was the HMBC spectrum of salvianolic acid T, A:
(R)-salvianolic acid T; B: (S)-salvianolic acid T.
FIG. 9 was the CD spectrum of salvianolic acid T, A:
(R)-salvianolic acid T; B: (S)-salvianolic acid T.
FIG. 10 was the comparison of CD spectrum and ECD simulated
spectrum, A: (R)-salvianolic acid T; B: (S)-salvianolic acid T.
FIG. 11 was the chromatogram of Salvianolic acids and tanshinones
(detective wavelength at 281 nm).
FIG. 12 was the chromatogram of saponines.
DETAILED EMBODIMENTS
In an embodiment of this invention, the present invention is to
provide a traditional Chinese medicine composition. Said
composition is composed of following materials by weight
percentage: 50.0%.about.99.9% of Salvia Miltiorrhiza and Panax
Notoginseng extract and 0.1%.about.50.0% of borneol. Wherein, the
Salvia Miltiorrhiza and Panax Notoginseng extract comprises
following ingredients by weight percentage:
Danshensu:Salvianolic acid T:protocatechuic aldehyde:Salvianolic
acid D:rosmarinic acid:Salvianolic acid B:Salvianolic acid A:Panax
Notoginseng Saponin R1:Ginsenoside Rg1:Ginsenoside Re:Ginsenoside
Rb1:Ginsenoside Rd:dihydrotanshinone I:tanshinone
I:cryptotanshinone:tanshinone
IIA=(2.about.5):(0.5.about.1.9):(1.1.about.3):(0.2.about.1.2):(0.2.about.-
1):(0.5.about.2):(0.5.about.2):(0.2.about.1):(1.5.about.4):(0.1.about.0.5)-
:(1.about.3.9):(0.1.about.1):(0.01.about.0.05):(0.05.about.0.1):(0.02.abou-
t.0.1):(0.1.about.0.5).
Preferably, said composition is composed of following materials by
weight percentage: 75.0%.about.99.9% of Salvia Miltiorrhiza and
Panax Notoginseng extract and 0.1%.about.25.0% of borneol.
More preferably, said composition is composed of following
materials by weight percentage: 90.0%.about.99.9% of Salvia
Miltiorrhiza and Panax Notoginseng extract and 0.1%.about.10.0% of
borneol.
Preferably, the Salvia Miltiorrhiza and Panax Notoginseng extract
comprises following ingredients by weight parts:
Danshensu:Salvianolic acid T:protocatechuic aldehyde:Salvianolic
acid D:rosmarinic acid:Salvianolic acid B:Salvianolic acid A:Panax
Notoginseng Saponin R1:Ginsenoside Rg1:Ginsenoside Re:Ginsenoside
Rb1:Ginsenoside Rd:dihydrotanshinone I:tanshinone
I:cryptotanshinone:tanshinone
IIA=(3.about.5):(0.8.about.1.5):(1.1.about.2.0):(0.5.about.1):(0.4.about.-
0.9):(1.about.2):(0.5.about.1.5):(0.4.about.1):(1.5.about.3):(0.1.about.0.-
5):(1.3.about.3):(0.1.about.0.8):(0.02.about.0.05):(0.05.about.0.1):(0.02.-
about.0.1):(0.15.about.0.4).
More preferably, the Salvia Miltiorrhiza and Panax Notoginseng
extract comprises following ingredients by weight parts:
Danshensu:Salvianolic acid T:protocatechuic aldehyde:Salvianolic
acid D:rosmarinic acid:Salvianolic acid B:Salvianolic acid A:Panax
Notoginseng Saponin R1:Ginsenoside Rg1:Ginsenoside Re:Ginsenoside
Rb1:Ginsenoside Rd:dihydrotanshinone I:tanshinone
I:cryptotanshinone:tanshinone
IIA=(3.1.about.4.2):(1.0.about.1.3):(1.5.about.1.9):(0.5.about.0.7):(0.5.-
about.0.9):(1.1.about.1.6):(0.7.about.1.2):(0.5.about.0.9):(1.9.about.2.5)-
:(0.2.about.0.4):(1.6.about.2.2):(0.2.about.0.6):(0.03.about.0.04):(0.07.a-
bout.0.08):(0.05.about.0.06):(0.26.about.0.28).
Further preferably, the Salvia Miltiorrhiza and Panax Notoginseng
extract comprises following ingredients by weight parts:
Danshensu:Salvianolic acid T:protocatechuic aldehyde:Salvianolic
acid D:rosmarinic acid:Salvianolic acid B:Salvianolic acid A:Panax
Notoginseng Saponin R1:Ginsenoside Rg1:Ginsenoside Re:Ginsenoside
Rb1:Ginsenoside Rd:dihydrotanshinone I:tanshinone
I:cryptotanshinone:tanshinone
IIA=3.7:1.1:1.7:0.6:0.7:1.3:0.9:0.7:2.3:0.3:1.9:0.4:0.03:0.07:0.06:0.27.
In an embodiment of this invention, aforesaid traditional Chinese
medicine composition is prepared by extracting Salvia Miltiorrhiza
and Panax Notoginseng to give the extract, adding the borneol into
the extract and mixing to have the product.
Preferably, the traditional Chinese medicine is prepared by the
following method: (1) Decocting Salvia Miltiorrhiza and Panax
Notoginseng with water under alkaline conditions to give the
decoction, filtering the decoction, concentrating and precipitating
the filtrate with alcohol to get the supernatant, filtering the
supernatant, recovering the alcohol to give the extract (or further
drying the extract), namely the Salvia Miltiorrhiza and Panax
Notoginseng extract; (2) Adding the extract of above step with
borneol and mixing uniformly. (3)
Wherein, Salvia Miltiorrhiza and Panax Notoginseng may be decocted
with water under alkaline condition either alone, or in
combination.
Preferably, the Salvia Miltiorrhiza and Panax Notoginseng extract
is prepared by following method: (1) Under alkaline conditions,
Salvia Miltiorrhiza and Panax Notoginseng are decocted with water
and filtered to give the residue for later use, the filtrate is
concentrated and precipitated with ethanol, and the supernatant is
filtered and ethanol is recovered to get extract I; (2) Resultant
residue is decocted with ethanol and ethanol is recovered to get
extract II; (3) Aforesaid extract II is dissolved with aqueous
ethanol, eluted with macroporous resin column and allowed to stand
still for full absorption by resin; the resin column is desorbed by
elution with aqueous ethanol until the eluent is colorless; the
eluent is collected and ethanol is recovered to give extract
III;
(4) The extracts I and III are mixed uniformly to have the Salvia
Miltiorrhiza and Panax Notoginseng extract.
Further preferably, the Salvia Miltiorrhiza and Panax Notoginseng
extract is prepared by following method: (1) Under alkaline
conditions, Salvia Miltiorrhiza and Panax Notoginseng are decocted
with water for 1.about.3 times, 1.about.3 hours each time and
filtered to give the filtrate I and the residue I; the residue I is
decocted with water for 1.about.3 times, 1.about.3 hours each time
and filtered to give the filtrate II and the residue II; the
filtrates I and II are combined, concentrated, precipitated with
70%.about.100%, preferable 95% ethanol to make the final
concentration of ethanol preferably to 60%.about.75% and allowed to
stand still; the supernatant is taken, filtered and ethanol is
recovered to give the extract I; (2) Resultant residue II is
extracted with ethanol for 1.about.3 times, 1.about.3 hours each
time, filtered and ethanol is recovered to give the extract II; (3)
Aforesaid extract II is dissolved with ethanol solution
(50%.about.70%), followed by elution with the macroporous resin
column that is allowed to stand still for 4.about.6 hours for full
absorption by resin; the resin column is desorbed by elution with
aqueous ethanol (70%.about.95%) until the eluent is colorless; the
eluent is collected and ethanol is recovered to give the extract
III; and (4) The extracts I and III are mixed uniformly to have the
Salvia Miltiorrhiza and Panax Notoginseng extract.
Wherein, said alkaline water solution includes, but not limited to,
one or more of sodium bicarbonate, sodium carbonate, sodium
hydrogen phosphate, sodium dihydrogen phosphate, sodium hydroxide,
potassium hydroxide and magnesium hydroxide with the pH value of
7.5.about.9.0; the concentration of the alkaline water solution is
1.about.4.5 wt %, preferably 2.25.about.3 wt %, ensuring that
Danshensu and salvainolic acid T can be extracted totally.
More preferably, the Salvia Miltiorrhiza and Panax Notoginseng
extract is prepared by following method: (1) Salvia Miltiorrhiza is
cut into the parts of 1.about.2 cm, and Panax Notoginseng is ground
into the particles of 0.18 cm; sodium bicarbonate accounting for
2.25.about.3 wt % of total crude medicine is weighed and charged
into an extracting tank together with weighed Salvia Miltiorrhiza
and Panax Notoginseng; in each tank, 5 times of water is added to
heat and keep boiling for 2 h.+-.20 min and filtered to give the
filtrate I and the residue I; said residue I is extracted for
2.sup.nd time with 4 times of water to heat and keep boiling for 1
h.+-.15 min and filtered to give the filtrate II and the residue
II; the filtrates I and II are combined, concentrated under reduced
pressure to a relative density of 1.16.about.1.20 (80.+-.5.degree.
C.) or a sugar degree of 48.about.52% to give concentrated liquid;
the concentrated liquid is transferred to an alcohol precipitation
tank, into which a proper amount of ethanol is poured to make final
content of ethanol to 65.about.70% and allowed to stand still for
12.about.24 hours to precipitate completely; the supernatant is
separated, the deposit is eliminated and the supernatant is
concentrated to give the extract I; (2) Said residue II is
extracted with ethanol for 2 times, 2 hours for each time, filtered
and the ethanol is recovered to give the extract II; (3) Aforesaid
extract II is dissolved with ethanol solution (70%), followed by
elution with the macroporous resin column that is allowed to stand
still for 5 hours for full absorption by resin; the resin column is
desorbed by elution with aqueous ethanol (95%) until the eluent is
colorless; the eluent is collected and ethanol is recovered to give
the extract III; and (4) The extracts I and III are mixed uniformly
to have the Salvia Miltiorrhiza and Panax Notoginseng extract.
Wherein, in step (1), 5 times of water means that the water is 5
times of total crude medicine in weight. Similarly, in step (2), 4
times of water means that the water is 4 times of total residue in
weight. Said macroporous resin is nonpolar resin, for example
HPD-100, HPD-400, HPD-700, preferable the HPD-100.
In an embodiment of this invention, said traditional Chinese
medicine composition is prepared by following crude medicine by
weight parts: Salvia Miltiorrhiza 75.about.90 parts, Panax
Notoginseng 10.about.25 parts and Borneol 0.1.about.4 parts.
Preferably, said traditional Chinese medicine composition is
prepared by following crude medicine by weight parts: Salvia
Miltiorrhiza 80.about.86 parts, Panax Notoginseng 15.about.18 parts
and Borneol 0.2.about.2 parts.
Most preferably, said traditional Chinese medicine composition is
prepared by following crude medicine by weight parts: Salvia
Miltiorrhiza 82.about.84 parts, Panax Notoginseng 16.about.17 parts
and Borneol 0.4.about.1.2 parts.
In an embodiment of this invention, said traditional Chinese
medicine composition is either extract or powder.
In an embodiment of this invention, during the process for
detecting the bioactive ingredients of Salvia Miltiorrhiza and
Panax Notoginseng extract, it is first time to discover bioactive
ingredients in aforesaid ratio by weight, and first time to
separate and obtain new compound of salvianolic acid T.
In an embodiment of this invention, the structure of new compound
of salvianolic acid was identified in its physicochemical
properties, high resolution mass spectrum (QFT-ESI), electrospray
ionization mass spectrum (ESI-MS), .sup.1H-NMR, .sup.13C-NMR, DEPT,
COSY, HMBC, HMQC and CD spectra (FIGS. 1-10).
The structure of the new compound of salvianolic acid is
represented by the general formula (I) as follows,
##STR00001##
.sup.1H-NMR shows 1 signal of methenyl proton attached to oxygen at
.delta. 4.93 (1H, dd, 8.0, 4.5 Hz); 11 signals of aromatic proton
at .delta. 6.85 (1H, d, 8.5 Hz), .delta. 7.31 (1H, d, 8.5 Hz),
.delta. 7.41 (1H, d, 15.5 Hz), .delta. 6.27 (1H, d, 15.5 Hz),
.delta. 6.62 (1H, s), .delta. 6.63 (1H, d, 8.0 Hz), .delta. 6.47
(1H, d, 8.0 Hz), .delta. 6.44 (1H, d, 2.0 Hz), .delta. 6.55 (1H, d,
8.5 Hz), .delta. 6.43 (1H, dd, 8.5, 2.0 Hz), .delta. 7.69 (1H, s);
2 signals of aliphatic proton at .delta. 2.89 (2H, ddd, 14.0, 8.0,
4.5 Hz).
Carbon-13 nuclear magnetic resonance .sup.13C-NMR spectrum shows 27
carbon signals, including 1 aliphatic carbon signal at .delta.
36.0, 1 signal of methenyl carbon attached to oxygen at .delta.
72.8, 3 signals of carbonyl carbon at .delta. 166.0, .delta. 170.6,
.delta. 168.4 and 22 signals of double-bond carbon at .delta.
123.7, .delta. 126.4, .delta. 142.9, .delta. 147.7, .delta. 115.0,
.delta. 118.4, .delta. 143.7, .delta. 113.9, .delta. 127.1, .delta.
116.5, .delta. 143.9, .delta. 144.8, .delta. 115.5, .delta. 120.0,
.delta. 126.0, .delta. 117.3, .delta. 144.8, .delta. 147.2, .delta.
115.3, .delta. 122.9, .delta. 141.1, .delta. 123.4.
In an embodiment of this invention, said compound of the present
invention has 2 isomers with optical rotation respectively at
-157.5.degree. and 196.6.degree.. Compound with C-8' absolute
configuration set as S/R-configuration is obtained through
molecular optimum design and calculated by BPV86 method having
TD-SCF with (2d, p) basis sets to read comparison between result
and experimental CD spectrum of the compound. It is inferred by the
substantially matched CD spectra that the absolute configuration of
C-8' in 2 isomers of the compound of the present invention are S
configuration and R configuration (see FIG. 10). The spectrum by
HMBC of the compound in the present invention is presented as
follows:
##STR00002##
Said salvianolic acid T is prepared by the following method: a)
extraction: extracting Salviae Miltiorrhiza crude drug or a mixture
of Salviae Miltiorrhiza and other crude drugs with water and
filtering, concentrating the filtrate, adding alcohol to
precipitate and obtain a supernatant, then concentrating the
supernatant to obtain an extract; b) separation: dissolving the
extract of the step a) in water, applying on the macroporous
absorbent resin, eluting the resin with acidic solution to remove
the impurities and then eluting with ethanol to obtain an ethanol
eluent, concentrating the ethanol eluent to obtain an extract; c)
purification: purifying the extract of the step b) with
high-pressure preparative LC; stationary phase is C18
reversed-phase silica column; mobile phase is
acetonitrile-water-formic acid by isocratic elution or gradient
elution method with detective wavelength at 280 nm; HPLC is used to
monitor the process of elution to collect the eluent containing the
salvianolic acid T; after being concentrated, the salvianolic acid
T is obtained.
In an embodiment of this invention, the preparation of said
traditional Chinese medicine composition is provided, and said
preparation of the present invention comprises the traditional
Chinese medicine composition and one or more kinds of
pharmaceutically acceptable carriers. Said traditional Chinese
medicine composition may account for 0.1.about.99.9 wt % of said
preparation, and the balanced is pharmaceutically acceptable
carrier.
In an embodiment of this invention, the composition is prepared in
the form of unit dosage and said unit dosage refers to individual
preparation, e.g. each tablet of tablets, each capsule of capsules,
each bottle of oral solutions and each bag of granules etc, and is
prepared by any one of methods known in pharmaceutical field. All
methods include the step of combining traditional Chinese medicine
composition with the carriers. Said carriers are composed of one or
more kinds of adjuvants. In general speaking, said preparation is
prepared by the following method: uniformly and tightly combining
said traditional Chinese medicine composition with liquid carrier,
finely ground solid carrier or mixture of both to give the outcome,
and, if necessary, preparing the outcome into desirable dosage
form. Usually, standard pharmaceutical techniques may be used,
which includes combining said traditional Chinese medicine
composition with pharmaceutically acceptable carrier to prepare
them into the pharmaceutical dosage form of the present invention.
These methods include steps of mixing, granulating and tableting.
Known to the person skilled in the prior art, the form and
characteristic of said pharmaceutically acceptable carrier or
diluting agent depend on the quantity of bio-active ingredients to
be mixed, administration route of preparation and other known
factors.
In an embodiment of this invention, said composition can be
prepared in any pharmaceutically acceptable dosage form, including
the tablet such as sugar-coated tablet, film-coated tablet and
enteric-coated tablet, the capsule such as soft capsule and hard
capsule, the oral liquid solution, the buccal tablet, the granules,
the instant powder, the pill, the pulvis, the paste such as
ointment and plaster, the Dan, the suspension, the powder, the
solution, the injection, the suppository, the cream, the ointment,
the plaster, the spray, the drop, the drop pill and the patch,
preferably the orally-administrated dosage form, such as the
capsule, the tablet, the oral solution, the granule, the pill, the
powder, the Dan and the ointment etc.
In an embodiment of this invention, said orally-administrated
dosage form includes carriers such as the adhesive, filling agent,
diluent, tableting agent, lubricant, disintegrating agent, colorant
agent, flavoring agent, wetting agent. If necessary, the tablet may
be coated.
In an embodiment of this invention, said filling agents include
cellulose, mannitol, lactose and other analogous filling agent.
Suitable disintegrating agents include starch, polyvinylpyrrolidone
(PVP) and starch derivative (e.g., sodium hydroxyethyl starch).
Suitable lubricants include magnesium stearate. Suitable wetting
agents include sodium dodecyl sulfate.
In an embodiment of this invention, oral solid preparations of said
composition can be prepared by blending repeatedly to make the
bio-active ingredients (API) distributed uniformly into a large
number of filling agent.
In an embodiment of this invention, oral liquid preparations are in
dosage form of either water-soluble or oil-soluble suspension,
solution, emulsion, syrup or elixir, or drying powder that is
always reconstituted with water or other suitable solvent before
clinical use. This liquid preparation may contain conventional
excipients, for example suspending agent, e.g. sorbitol, syrup,
methylcellulose, gelatin, hydroxy ethyl cellulose, carboxy methyl
cellulose, aluminum stearate gel or hydrogenated edible fat;
emulsifying-agent, e.g lecithin, sorbitan monoleate or arabic gum;
non-aqueous excipient (including edible oil) e.g. almond oil,
fractionated coconut oil, oil ester such as glyceride; propylene
glycol or ethanol; as well as preservative e.g. methylparaben,
nipasol, sorbic acid. If necessary, conventional flavoring agent or
colorant agent can be included.
In an embodiment of this invention, said injection contains
bio-active components and aseptic excipients. To the person skilled
in the prior art, said bio-active component is dissolved or
suspended in the liquid according to the type and concentration of
excipients. Generally, solution is prepared by dissolving the
bio-active components in the excipients, sterilizing, loading into
a suitable vial or ampoule and sealing. Some pharmaceutically
acceptable adjuvant, e.g. local anaesthetic, preservative and
buffering agent can be added as required. In order to improve its
stability, before loaded into the vial, this composition of the
present invention can be frozen and treated in vacuum to remove
water.
In an embodiment of this invention, said traditional Chinese
medicine composition can be prepared by optionally adding
pharmaceutically acceptable excipients. Said excipients are
selected from: mannitol, sorbitol; sodium thiosulfate; cysteine
hydrochloride, mercaptoacetic acid, methionine, Vitamin C; EDTA
disodium, EDTA calcium disodium salt; monovalent alkali carbonate,
acetate, phosphate or its aqueous solution; hydrochloride, acetic
acid, sulfuric acid, phosphoric acid; amino acid; sodium chloride,
potassium chloride, sodium lactate; xylitol; maltose, glucose,
fructose, dextran; glycine; starch, sucrose, lactose, mannitol;
silicon derivative; cellulose and its derivatives; alginate;
gelatin; PVP, glycerol; Tween-80, agar gel; calcium carbonate,
calcium bicarbonate; surfactant; PEG; cyclodextrin; phospholipids;
Kaolin; talcum powder, calcium stearate, magnesium stearate; and
the like.
Preferably, said composition is prepared into the drop pill, more
preferably the micro drop pill.
In an embodiment of this invention, a compound Salvia micro drop
pill (CSMDP) is provided and said CSMDP is prepared with
traditional Chinese medicine composition and the micro drop pill
matrix in a ratio of 1:5.about.5:1 by weight, preferably prepared
with traditional Chinese medicine composition and the micro drop
pill matrix in a ratio of 1:3.about.3:1 by weight, most preferably
in a ratio of 1:(1.about.3).
In an embodiment of this invention, the preparation method for
preparing CSMDP comprises following steps: (1) Material melting
step: charging the medicine and drop pill matrix into a
homogenizer, mixing homogenously at 1000.about.5000 rpm for
1.about.200 min, melting homogenously at 3000.about.10000 rpm for
1.about.100 min; during the melting process, the temperature is
kept at 60.about.100.degree. C. to obtain the molten medicine
liquid; the ratio of the medicine to the micro drop pill matrix is
1:5.about.5:1 by weight; (2) Dropping step: delivering the molten
medicine liquid to a dripper, and acquiring medicine drops from the
dripper by means of vibration dropping at a vibration frequency of
2.about.2000 Hz under a dropping pressure of 0.5.about.4.0 Bar,
with an acceleration at 1.about.20 G; and the temperature of the
dripper is at 70.degree. C..about.300.degree. C.; the dropping rate
is matched with the melting rate in step (1); and (3) Condensation
step: cooling the medicine drops with cooling gas rapidly to
solidify and obtaining solid drop pill having a particle size of
0.2 mm.about.4.0 mm; the temperature of the cooling gas is
0.degree. C. or lower.
Preferably, the preparation method for preparing CSMDP comprises
following steps: (1) Material melting step: charging the medicine
and matrix into a homogenizer, mixing homogenously at
1000.about.5000 rpm for 1.about.200 min, melting homogenously at
3000.about.10000 rpm for 1.about.100 min; during the melting
process, the temperature is kept at 60.about.100.degree. C. to
obtain the molten medicine liquid; the ratio of medicine to the
micro drop pill matrix is 1:3.about.3:1 by weight; (2) Dropping
step: delivering the molten medicine liquid to a dripper, and
acquiring medicine drops from the dripper by means of vibration
dropping at a vibration frequency of 20.about.300 Hz under a
dropping pressure of 0.54.0 Bar, with an acceleration at 1.about.15
G; the temperature of the dripper is at 70.degree.
C..about.200.degree. C.; the dropping rate is matched with the
melting rate in step (1); and (3) Condensation step: cooling the
medicine drops with cooling gas rapidly to solidify and obtaining
the solid drop pill having a particle a size of 0.2 mm.about.4.0
mm; the temperature of the cooling gas is 0.degree. C. or
lower.
Wherein, in step (1), said drop pill matrix includes one or more of
PEG, sorbitol, xylitol, lactitol, maltose, starch, methylcellulose,
sodium carboxymethyl cellulose, hydroxypropyl methylcellulose
(HPMC), Arabic gum, alginate, dextrin, cyclodextrin and agar,
preferably the solid PEG, e.g. PEG-1000, PEG-2000, PEG-3000,
PEG-4000, PEG-5000, PEG-6000, PEG-7000 and PEG-8000, more
preferably one or more of the PEG-1000, PEG-2000, PEG-3000,
PEG-4000, PEG-6000, PEG-8000, most preferably the PEG-6000,
PEG-4000, or the combination of PEG-4000 and PEG-6000. In step (1),
homogenization may enhance content uniformity, and RSD is improved
from previous 10% to 7%.
Preferably, in step (1), said ratio of medicine to drop pill matrix
is 1:3.about.3:1 by weight, mixing homogeneously 3000.about.5000
rpm for 10.about.60 min and melting homogeneously at
4000.about.9000 rpm for 5.about.30 min, and during the melting
process the temperature is kept at 7090.degree. C.; most
preferably, said ratio of medicine to the matrix is 1:(1.about.3)
by weight, mixing homogeneously 3000.about.4000 rpm for 10.about.30
min and melting homogeneously at 4000.about.6000 rpm for 6.about.30
min, and during the melting process the temperature is kept at
75.about.85.degree. C.
In step (2), preferably, said temperature of dripper is at
70.about.100.degree. C., preferably 75.about.85.degree. C.; the
vibration frequency at 50.about.300 Hz, preferably 100.about.200
Hz, more preferably 90.about.200 Hz, more preferably 130.about.140
Hz, most preferably 137 Hz; acceleration at 3.5.about.4.5 G
preferably 4.0 G; dropping pressure at 1.0.about.3.0 Bar,
preferably 1.8 Bar; dropping rate is 10.about.14 Kg/h, preferably
12.about.30 Kg/h, further preferably 15.about.25 Kg/h.
In step (3), said condensation by cooling gas means that the
falling drops are cooled by using low-temperature condensate trap
to make solidification. Said temperature of cooling gas is
0.degree. C. or lower, preferably at 0.about.-150.degree. C.,
further preferably -60.degree. C..about.-140.degree. C., most
preferably -80.degree. C..about.-120.degree. C.; said cooling gas
is air, nitrogen or inert gas; said particle size of micro drop
pill is 1.0 mm.about.2.0 mm.
Further, said method may additionally comprise step (4) of drying
step: fluidized-bed drying equipment is preferred at
-20.about.100.degree. C., preferably drying at -20.about.90.degree.
C. for 1.about.4 hours to obtain the blank drop pill. Especially,
fluidized-bed drying the low-temperature drop pill from step (3) is
performed at 40.about.150.degree. C., preferably
40.about.60.degree. C. for 1.about.4 hours, preferably 1.about.3
hours, most preferably 2 hours, to obtain the blank drop pill.
In step (4), gradient-rising temperature drying method is
preferred, including steps of: fluidizing at -20.about.30.degree.
C., drying at 15.about.35.degree. C. for 10.about.120 min, drying
at 35.about.55.degree. C. for 10.about.60 min, drying at
55.about.100.degree. C. for 0.about.60 min; preferably fluidizing
at 0.about.20.degree. C., drying at 25.degree. C. for 60 min,
drying at 45.degree. C. for 30 min, drying at 55.degree. C. for
0.about.30 min. In this step, the drop pills are in state of
fluidization, not only solving the problems of drop pill adhesion,
but also enhancing the efficiency and productivity up to 30
kg/h.
In step (4), by screening through a large number of the drying
methods, the inventors found that: in step (3), the blank pill is
dried by one of following drying methods: the low-humidity airing
method, coating pot drying method, vacuum oven drying method,
hot-air blasting drying method, track microwave heating drying
method, fluidization drying coating method. In terms of yield and
productivity, the coating pot drying method, track microwave
heating drying method and fluidization drying coating method are
preferred. In terms of the industrialization, the fluidization bed
drying method is preferred, and the fluidization drying coating
method is more preferred. Advantages and disadvantages of various
drying methods are shown in Table 1.
TABLE-US-00001 TABLE 1 No. Drying mode Advantages Disadvantages 1
Low-temperature High yield. The yield (1) Stringent requirement for
drying airing is usually about 95% environment, demanding the
air-circulated without consideration clean workshop with the
relative humidity of dropping factors. less than 30%, temperature
20.degree. C. or more; (2) Prolonged drying period, 48 hours
required when thickness of drop pill is up to about 2 cm; (3) Large
area workshop occupied; (4) Turning regularly; (5) Exposing for
long time, prone to pollution. 2 Coating pot (1) High yield. The
(1) Demanding the inlet air having low drying yield is usually
about humidity, generally not more than 5 g/kg; 95% without (2) Low
drying efficiency at least 6 h/batch; consideration of (3)
Customerized device; dropping factors; (4) Easily resulting in
product rejection (2) Drying and coating due to the adhesion of
drop pills. can be achieved simutaneously. 3 Vacuum oven None (1)
Low drying efficiency, demanding drying longtime low-temperature
vacuum drying, at least 30 hours/batch; (2) Low-productivity
device, the productivity of oven per square meter is difficult to
exceed 0.2 kg/h; (3) Easily resulting in adhesion and deformation
of drop pill, which is not round in appearance. 4 Hot-air blasting
None (1) Low drying efficiency, demanding drying low-temperature
drying for long time, at least 40 hours/batch; (2) Low-productivity
device, the productivity of oven per square meter is difficult to
exceed 0.1 kg/h; (3) Easily resulting in adhesion and deformation
of drop pill, which is not round in appearance; (4) Drying workshop
with relative humidity of less than 30%. 5 Track microwave High
yield, reaching (1) Difficult to control the drying process,
heating drying 20 Kg/h. easily resulting in adhesion and
deformation of drop pill, which is not round in appearance, or
product rejection due to charring; (2) Relative humidity less than
30% in drying workshop; (3) Unable to solve residual microwave in
product. 6 Fluidization (1) High yield, Inlet air humidity should
be controlled, drying coating reaching 30 kg/h; generally not more
than 7.5 g/kg. drying (2) Drying and coating simultaneously; (3)
Round drop pill in appearance; (4) High yield. The yield is usually
over 98% without consideration of dropping factors; (5) Easily
controlled during drying, real- time displaying the water
content.
Further, said preparation method for micro drop pill may
additionally comprise step (5) of coating: coating the blank pill
obtained from step (4) in a state of fluidization at
30.about.65.degree. C.; the concentration of coating liquid is at
5.about.25 wt %, preferably 18.about.20 wt %; the coating material
is selected from shellac, CAP (cellulose acetate phthalate), methyl
acrylate, methyl methacrylate or opadry; the ratio of coating
material to the blank pill is 1:50.about.1:10, preferably
1:50.about.1:25.
In order to better implement the preparation method for micro drop
pill, preferably, said method may additionally comprise a premixing
step before step (1): adding the medicine powder or extract with
water, stirring over 10 min at 30.about.80.degree. C. to obtain the
premixed material, ensuring the homogenization of water. This step
may remedy the defects brought about by inputted dried powder.
In an embodiment of this invention, said micro drop pills prepared
by the method may be either packaged directly, or prepared into
capsule after loading into capsule shell. After preparation of
capsule, the weighing step for capsule may be additionally employed
one by one. High-speed weighing for the loaded capsule one-by-one
before packaging is employed so as to eliminate possibly
substandard capsules.
In an embodiment of this invention, said method is characterized in
that: it is the first time to creatively combine the techniques of
vibration dropping and air cooling with the fluidization drying
coating method to apply to the formulation of drop pill and drop
pill capsule. Hence, both producing rate and forming quality of the
drop pill are increased, further simplifying the production
process. The advantages of the present invention are presented as
follows: 1. Using method of vibration dropping and air cooling
instead of traditional drop pill preparation method
(gravity/pressure dropping and coolant cooling)
Utilization of air cooling well met the requirements of high-speed
dropping, preparing a micro drop pill (with the particle size of
2.5 mm or smaller) and increasing drug-loading capacity. As a
result of this, the drug-loading capacity of drop pill had been
increased exponentially and the amount and dose of the drop pill
matrix reduced dramatically. Moreover, the productivity of the drop
pills had been enhanced greatly from traditional rate of 1.about.2
pills/s to 1000.about.1250 pills/s, and the particle size ranged
from 2 mm.about.4 mm to 0.2 mm.about.4 mm. It was possible to
produce the micro drop pills that could be loaded into the capsule.
By adjusting the vibration parameters and fluidization coating, the
drug-loading capacity would be increased from about 25%
traditionally to about 50% or more, and therefore the amount of
matrix reduced by leaps and bounds. 1. Lowered cost: instead of the
traditional coolant of liquid paraffin and silicone oil etc, the
low-temperature air, nitrogen or inert gas were employed to perform
cooling, avoiding follow-up steps of eliminating residual solvent
(e.g. step of removing oil). Hence, the operation process was
simplified and totally free of residual organic solvent. The
preparation cost was lowered. 2. The fluidization drying was added,
which might not only prevent the drop pill from adhesion,
precipitation of constituents and reduced volatile oil caused by
the storage stage of air cooling method, but also reduce drying
time (from 4.about.24 hours to 2 hours). By using fluidization
coating, the molten medicine liquid was injected to coat with
drug-loading, further improving the drug-loading capacity. Also,
this technique of injection was used for coating the drop pills so
as to realize the purposes of different techniques (e.g. the
sustained release coating, film coating and sugar coating etc).
Because the fluidization was believed to be a mild process, it not
only ensured the water to reach a stable value, but also improved
the drug-loading capacity and the uniformity of coating in the drop
pills. Unlike the drop pills prepared by the traditional methods,
the fluidization would prevent the drop pills from being cleft and
white-dotted and at same time, the yield was increased.
Comparison of the physico-chemical parameters between the micro
drop pill of the present invention (CSDP prepared by the method of
Example 15) and traditional drop pill was presented in Table 2.
TABLE-US-00002 TABLE 2 Micro drop pill in the present invention
Commercially available drop pills Weight & Smaller weight,
about 4 mg, so as to Larger weight, 25 mg~27 mg volume be
accurately filled into capsule Drug-loading Drug-loading 30 wt %
(calculated Drug-loading 18-20 wt % (calculated capacity based on
dried extract) based on dried extract) Appearance Replacing the
original cooling liquid Residual cooling liquids on the with air
cooling, ensuring surface of drop pill condensation forming effect,
overcoming the drawbacks of residual cooling liquids Efficiency
Super high-speed vibration and Slower dropping rate than the
pressurized dropping ensuring a vibration dropping, complicated
stable delivery of materials, process of eliminating the cooling
increasing dropping rate, greatly liquids on the surface, requiring
long improving the efficiency time Release rate Totally mixing the
medicine with the -- matrix by homogenizer, dispersing the medicine
active ingredients, helping drug absorption, reducing the pill
weight so as to not only be accurately filled into capsule, but
also quicken drug release, enhancing clinical efficacy Roundness
& Excellent roundness, the particle size Good roundness,
particle size of particle size of 1 mm~2 mm, capable of preparing 3
mm~4 mm, unable to reach drop pills having a particle size of 1
mm~2 mm 0.2 mm~4 mm
EXAMPLES
The following examples are offered for purposes of elaborating
explanation of the present invention only and are not intended to
limit the scope of the invention in any way.
Determination method of Salvia Miltiorrhiza and Panax Notoginseng
extract
In following Examples, each ingredient of the traditional Chinese
medicine was determined by following method, including the
Danshensu, Salvianolic acid T, protocatechuic aldehyde, Salvianolic
acid D, rosmarinic acid, Salvianolic acid B, Salvianolic acid A,
dihydrotanshinone I, tanshinone I, cryptotanshinone, tanshinone
IIA, Panax Notoginseng Saponin R1, Ginsenoside Rg1, Ginsenoside Re,
Ginsenoside Rb1 and Ginsenoside Rd.
Determination of Salvianolic Acids and Tanshinones
Preparation of Reference and Tested Solutions
Preparation of reference solution: a certain amount of reference
substances, including the Danshensu, Salvianolic acid T,
protocatechuic aldehyde, Salvianolic acid D, rosmarinic acid,
Salvianolic acid B, Salvianolic acid A, dihydrotanshinone I,
tanshinone I, cryptotanshinone, tanshinone IIA, were weighed
accurately, transferred to 10 ml volumetric flask and diluted with
methanol to the scale, which was continued to be diluted as
required, shook well and filtered through 0.22 .mu.m membrane to
give the reference solution respectively as follows: Danshensu at
0.0315 mg/ml, Salvianolic acid T at 0.04596 mg/ml, protocatechuic
aldehyde at 0.07556 mg/ml, Salvianolic acid D at 0.04385 mg/ml,
rosmarinic acid at 0.04263 mg/ml, Salvianolic acid B at 0.04248
mg/ml, Salvianolic acid A at 0.1118 mg/ml, dihydrotanshinone I at
0.02098 mg/ml, tanshinone I at 0.02085 mg/ml, cryptotanshinone at
0.02442 mg/ml, tanshinone IIA at 0.01992 mg/ml.
Preparation of tested solution: 0.1 g of Salvia Miltiorrhiza and
Panax Notoginseng extract was weighed accurately, transferred to 10
ml volumetric flask, dissolved with purified water, diluted to
scale and filtered through 0.22 .mu.m membrane to give the tested
solution.
Method: 10 .mu.l of reference and tested solutions were
respectively absorbed with precision and injected into HPLC to
assay.
Chromatographic column: Agilent Zorbax SB C18 (4.6.times.250 mm, 5
.mu.m);
Flow rate: 0.5 mL/min
Column temperature: 30.degree. C.
Detective wavelength: 281 nm,
The eluting condition was presented in following Table 3.
TABLE-US-00003 TABLE 3 A (%) B (%) Time Water (0.02% Acetonitrile
(0.02% (min) formic acid) formic acid) 0 90 10 15 80 20 25 75 25 30
74 26 45 54 46 50 48 52 62 28 72 70 0 100 76 0 100
Wherein, the retention time of Danshensu, Salvianolic acid T,
protocatechuic aldehyde, Salvianolic acid D, rosmarinic acid,
Salvianolic acid B, Salvianolic acid A, dihydrotanshinone I,
tanshinone I, cryptotanshinone and tanshinone IIA under wavelength
of 281 nm was presented in FIG. 11 and Table 4.
TABLE-US-00004 TABLE 4 Grouping of Retention ingredients time (min)
Peak name Salvianolic acids 9.670 Danshensu 16.914 protocatechuic
aldehyde 26.276 Salvianolic acid T 28.556 Salvianolic acid D 32.696
rosmarinic acid 35.927 Salvianolic acid B 40.831 Salvianolic acid A
Tanshinones 66.761 dihydrotanshinone I 71.469 tanshinone I 71.971
Cryptotanshinone 74.973 tanshinone IIA
Determination of Saponins
Preparation of reference solution: a certain amount of reference
substances, including the Panax Notoginseng Saponin R1, Ginsenoside
Rg1, Ginsenoside Re, Ginsenoside Rb1 and Ginsenoside Rd, were
weighed accurately, into which methanol was added to give the
reference solution, respectively containing 0.5 mg, 2.0 mg, 1.0 mg,
0.5 mg, 0.5 mg, 0.5 mg, 1.0 mg per ml.
Preparation of tested solution: 0.1 g of Salvia Miltiorrhiza and
Panax Notoginseng extract was weighed accurately, dissolved with 4%
ammonia solution (10 ml) and passed through D101 macro porous
column (inner diameter: 0.7 cm and height: 5 cm), which was eluted
firstly with 30 ml water, 30 ml methanol (30%) and 10 ml methanol
to collect the methanol solution in 10 volumetric flask, shake well
to give the tested solution.
Chromatographic condition and system suitability test:
octadecylsilane bonded silica gel was used as bulking agent;
acetonitrile was used as mobile phase "A" and water as mobile phase
"B". According to following Table 5, a gradient elution method was
used, and flow rate was at 1.0 ml/min, detective wavelength at 203
nm, column temperature at 30.degree. C. and recording time 75
min.
TABLE-US-00005 TABLE 5 mobile phase of gradient elution Time (min)
Mobile phase A Mobile phase B 0 20 80 25 25 75 60 40 60 70 70 30 75
20 80 80 20 80
Measurement: 10 .mu.l of reference and tested solutions were
respectively absorbed with precision and injected into HPLC to
assay under aforesaid conditions. The retention time of each
ingredient was presented in FIG. 12.
Preparation of Traditional Chinese Medicine Composition of the
Present Invention
Example 1
820 g of crude medicine of Salvia Miltiorrhiza was cut into the
pieces of 1.about.2 cm in length and 160 g of crude medicine of
Panax Notoginseng ground into particles of 0.18 cm. Sodium
bicarbonate accounting for 2.25.about.3 wt % of total crude
medicine was weighed and charged into an extracting tank together
with Salvia Miltiorrhiza and Panax Notoginseng and 5 times of water
was added to heat and keep boiling for 2 h and filtered to give the
filtrate I and residue I. Resultant residue I was extracted for
2.sup.nd time by adding with 4 times of water to heat and keep
boiling for 2 h and filtered to give the filtrate II and residue
II. The filtrates I and II were concentrated to a relative density
of 1.16.about.1.20 (80.+-.5.degree. C.) or a relative sugar degree
of 48.about.52% to give the concentrated liquid. The liquid was
delivered to the alcohol precipitation tank, into which a proper
amount of ethanol was poured to make final ethanol content of
65.about.70% and allowed to stand still for 12 hours to precipitate
completely. The supernatant was separated and the deposit
eliminated. The supernatant was concentrated to give the extract,
which was dried to obtain extract I.
The residue II was extracted with ethanol for 2 times, 2 hours for
each time and filtered. The ethanol was recovered to give the
extract II. Resultant extract II was dissolved with 70% ethanol,
eluted with HPD-100 macroporous resin column and allowed to stand
still for 5 hours for full absorption by resin. The resin column
was desorbed by elution with 95% ethanol until the eluent was
colorless; the eluent was collected and the ethanol was recovered
to give the extract III. The extract I and extract III were mixed
uniformly to give the Salvia Miltiorrhiza and Panax Notoginseng
extract.
By aforesaid method, the Salvia Miltiorrhiza and Panax Notoginseng
extract was determined and the concentration of ingredients was
presented as follows: the Danshensu at 37 mg/g, Salvianolic acid T
at 11 mg/g, protocatechuic aldehyde at 17 mg/g, Salvianolic acid D
at 6 mg/g, rosmarinic acid at 7 mg/g, Salvianolic acid B at 13
mg/g, Salvianolic acid A at 9 mg/g, Panax Notoginseng Saponin R1 at
17 mg/g, Ginsenoside Rg1 at 23 mg/g, Ginsenoside Re at 3 mg/g,
Ginsenoside Rb1 at 19 mg/g and Ginsenoside Rd at 4 mg/g,
dihydrotanshinone I at 0.3 mg/g, tanshinone I 0.7 mg/g,
cryptotanshinone at 0.6 mg/g, tanshinone IIA at 2.7 mg/g.
90 g of the Salvia Miltiorrhiza and Panax Notoginseng extract was
added with 9 g of borneol to give the traditional Chinese
medicine.
Example 2
75 g of Salvia Miltiorrhiza and Panax Notoginseng extract obtained
from Example 1 and 25 g of borneol was mixed uniformly to give the
traditional Chinese medicine composition.
800.0 g of crude medicine of Salvia Miltiorrhiza and 150.0 g of
Panax Notoginseng were decocted with water under alkaline condition
for 3 times (pH=9), 1 hour each time and filtered to give the
filtrate I and residue I. Resultant residue I was decocted with
water for 3 times, 1 hour each time and filtered to give the
filtrate II and residue II. The filtrate I and filtrate II were
combined and concentrated under reduced pressure to give the
concentrated liquid. The concentrated liquid was added into the
alcohol precipitation tank with addition of a proper amount of
ethanol to make final ethanol content of 70% and allowed to stand
still. The supernatant was taken and concentrated to obtain the
extract I.
The residue II was extracted with ethanol for 1 hour, 1 time and
filtered. The ethanol was recovered to give the extract II.
Resultant extract II was dissolved with 50% ethanol, eluted with
HPD-400 macroporous resin column and allowed to stand still for 4
hours for full absorption by resin. The resin column was desorbed
by elution with 70% ethanol until the eluent was colorless; the
eluent was collected and the ethanol was recovered to give the
extract III. The extract I and extract III were mixed uniformly to
give the Salvia Miltiorrhiza and Panax Notoginseng extract.
99.9 g of the Salvia Miltiorrhiza and Panax Notoginseng extract was
mixed uniformly with 0.1 g of borneol to give the traditional
Chinese medicine. By aforesaid method, the Salvia Miltiorrhiza and
Panax Notoginseng extract was determined to contain: the Danshensu
at 3.2 g, Salvianolic acid T at 1.7 g, protocatechuic aldehyde at
2.5 g, Salvianolic acid D at 0.9 g, rosmarinic acid at 1.2 g,
Salvianolic acid B at 2.1 g, Salvianolic acid A at 1.5 g, Panax
Notoginseng Saponin R1 at 1.2 g, Ginsenoside Rg1 at 3.3 g,
Ginsenoside Re at 0.5 g, Ginsenoside Rb1 at 2.9 g and Ginsenoside
Rd at 0.8 g, dihydrotanshinone I at 0.05 g, tanshinone I 0.1 g,
cryptotanshinone at 0.08 g, tanshinone IIA at 0.4 g.
90 g of Salvia Miltiorrhiza and Panax Notoginseng extract obtained
from Example 3 and 10 g of borneol was mixed uniformly to give the
traditional Chinese medicine composition.
750 g of crude medicine of Salvia Miltiorrhiza and 250 g of Panax
Notoginseng were decocted with water under alkaline condition for 2
times (pH=7.5), 2 hours each time and filtered to give the filtrate
I and residue I. Resultant residue I was decocted with water for 2
times, 2 hours each time and filtered to give the filtrate II and
residue II. The filtrate I and filtrate II were combined and
concentrated. The concentrated liquid was added with ethanol to
make final ethanol content of 70% and allowed to stand still. The
supernatant was filtered and the ethanol was recovered to obtain
the extract I.
The residue II was extracted with ethanol for 3 times, 1 hour for
each time and filtered. The ethanol was recovered to give the
extract II. Resultant extract II was dissolved with 60% ethanol,
eluted with HPD-700 macroporous resin column and allowed to stand
still for 6 hours for full absorption by resin. The resin column
was desorbed by elution with 80% ethanol until the eluent was
colorless; the eluent was collected and the ethanol was recovered
to give the extract III. The extract I and extract III were mixed
uniformly to give the Salvia Miltiorrhiza and Panax Notoginseng
extract.
90 g of the Salvia Miltiorrhiza and Panax Notoginseng extract was
mixed uniformly with 10 g of borneol to give the traditional
Chinese medicine. By aforesaid method, the Salvia Miltiorrhiza and
Panax Notoginseng extract contained the Danshensu, Salvianolic acid
T, protocatechuic aldehyde, Salvianolic acid D, rosmarinic acid,
Salvianolic acid B, Salvianolic acid A, Panax Notoginseng Saponin
R1, Ginsenoside Rg1, Ginsenoside Re, Ginsenoside Rb1, Ginsenoside
Rd, dihydrotanshinone I, tanshinone I, cryptotanshinone and
tanshinone IIA respectively at 3.6 g, 1.1 g, 1.8 g, 0.7 g, 0.8 g,
1.4 g, 1.1 g, 0.9 g, 2.5 g, 0.4 g, 1.9 g, 0.5 g, 0.04 g, 0.07 g,
0.07 g and 0.3 g.
82 g of crude medicine of Salvia Miltiorrhiza and 16 g of Panax
Notoginseng were decocted with water under alkaline condition for 2
times (pH=7.5), 2 hours each time and filtered to give the filtrate
I and residue I. Resultant residue I was decocted with water for 3
times, 3 hours each time and filtered to give the filtrate II and
residue II. The filtrate I and filtrate II were combined and
concentrated. The concentrated liquid was added with ethanol to
make final ethanol concentration of 70% and allowed to stand still.
The supernatant was filtered and the ethanol was recovered to
obtain the extract I.
The residue II was extracted with ethanol for 3 hours, 1 time and
filtered. The ethanol was recovered to give the extract II.
Resultant extract II was dissolved with 55% ethanol, eluted with
HPD-100 macroporous resin column and allowed to stand still for 4.5
hours for full absorption by resin. The resin column was desorbed
by elution with 90% ethanol until the eluent was colorless; the
eluent was collected and the ethanol was recovered to give the
extract III. The extract I and extract III were mixed uniformly to
give the Salvia Miltiorrhiza and Panax Notoginseng extract.
50 g of the Salvia Miltiorrhiza and Panax Notoginseng extract was
mixed uniformly with 50 g of borneol to give the traditional
Chinese medicine. By aforesaid method, the Salvia Miltiorrhiza and
Panax Notoginseng extract contained the Danshensu, Salvianolic acid
T, protocatechuic aldehyde, Salvianolic acid D, rosmarinic acid,
Salvianolic acid B, Salvianolic acid A, Panax Notoginseng Saponin
R1, Ginsenoside Rg1, Ginsenoside Re, Ginsenoside Rb1, Ginsenoside
Rd, dihydrotanshinone I, tanshinone I, cryptotanshinone and
tanshinone IIA respectively at 1.8 g, 0.5 g, 0.9 g, 0.3 g, 0.4 g,
0.7 g, 0.5 g, 0.4 g, 1.2 g, 0.2 g, 0.9 g, 0.2 g, 0.02 g, 0.04 g,
0.03 g and 0.1 g.
84 g of Salvia Miltiorrhiza and Panax Notoginseng extract obtained
from Example 6 and 18 g of borneol was mixed uniformly to give the
traditional Chinese medicine composition.
400 g of crude medicine of Salvia Miltiorrhiza was cut into the
pieces of 1.about.2 cm in length and 80 g of crude medicine of
Panax Notoginseng ground into particles. Sodium bicarbonate
accounting for 3 wt % of total crude medicine was weighed and
charged into an extracting tank together with Salvia Miltiorrhiza
and Panax Notoginseng and 5 times of water was added to heat and
keep boiling for 2 h and filtered to give the filtrate I and
residue I. Resultant residue I was extracted for 2.sup.nd time by
adding with 4 times of water to heat and keep boiling for 1 h and
filtered to give the filtrate II and residue II. The filtrates I
and II were combined and concentrated under reduced pressure to a
relative density of 1.16.about.1.20 (80.+-.5.degree. C.) or a
relative sugar degree of 50% to give the concentrated liquid. The
liquid was delivered to the alcohol precipitation tank, into which
a proper amount of ethanol was poured to make final ethanol content
of 68% and allowed to stand still for 20 hours to precipitate
completely. The supernatant was separated and the deposit was
eliminated. The supernatant was concentrated to give the extract
I.
The residue II was extracted with ethanol for 3 times, 1 hour for
each time and filtered. The ethanol was recovered to give the
extract II. Resultant extract II was dissolved with 65% ethanol,
eluted with HPD-100 macroporous resin column and allowed to stand
still for 5.5 hours for full absorption by resin. The resin column
was desorbed by elution with 90% ethanol until the eluent was
colorless; the eluent was collected and the ethanol was recovered
to give the extract III. The extract I and extract III were mixed
uniformly to give the Salvia Miltiorrhiza and Panax Notoginseng
extract.
By aforesaid method, the Salvia Miltiorrhiza and Panax Notoginseng
extract contained the Danshensu, Salvianolic acid T, protocatechuic
aldehyde, Salvianolic acid D, rosmarinic acid, Salvianolic acid B,
Salvianolic acid A, Panax Notoginseng Saponin R1, Ginsenoside Rg1,
Ginsenoside Re, Ginsenoside Rb1, Ginsenoside Rd dihydrotanshinone
I, tanshinone I, cryptotanshinone and tanshinone IIA respectively
at 20 mg/g, 5 mg/g, 11 mg/g, 2 mg/g, 2 mg/g, 5 mg/g, 5 mg/g, 2
mg/g, 5 mg/g, 1 mg/g, 1 mg/g, 1 mg/g, 0.1 mg/g, 0.5 mg/g, 0.2 mg/g,
1 mg/g.
90 g of the Salvia Miltiorrhiza and Panax Notoginseng extract was
added with 9 g of borneol to give the traditional Chinese
medicine.
Example 9
500 g of crude medicine of Salvia Miltiorrhiza was cut into the
pieces of 1.about.2 cm in length and 102 g of crude medicine of
Panax Notoginseng ground into particles. Sodium bicarbonate
accounting for 2.5 wt % of total crude medicine was weighed and
charged into an extracting tank together with Salvia Miltiorrhiza
and Panax Notoginseng and 6 times of water was added to heat and
keep boiling for 2 h and filtered to give the filtrate I and
residue I. Resultant residue I was extracted for 2.sup.nd time by
adding with 6 times of water to heat and keep boiling for 1 h and
filtered to give the filtrate II and residue II. The filtrates I
and II were combined and concentrated under reduced pressure to a
relative density of 1.16.about.1.20 (80.+-.5.degree. C.) or a
relative sugar degree of 48% to give the concentrated liquid. The
liquid was delivered to the alcohol precipitation tank, into which
a proper amount of ethanol was poured to make final ethanol content
of 65% and allowed to stand still for 24 hours to precipitate
completely. The supernatant was separated and the deposit was
eliminated. The supernatant was concentrated to give the extract
I.
The residue II was extracted with ethanol for 3 times, 2 hours for
each time and filtered. The ethanol was recovered to give the
extract II. Resultant extract II was dissolved with 55% ethanol,
eluted with HPD-700 macroporous resin column and allowed to stand
still for 4.5 hours for full absorption by resin. The resin column
was desorbed by elution with 75% ethanol until the eluent was
colorless; the eluent was collected and the ethanol was recovered
to give the extract III. The extract I and extract III were mixed
uniformly to give the Salvia Miltiorrhiza and Panax Notoginseng
extract.
By aforesaid method, the Salvia Miltiorrhiza and Panax Notoginseng
extract contained the Danshensu, Salvianolic acid T, protocatechuic
aldehyde, Salvianolic acid D, rosmarinic acid, Salvianolic acid B,
Salvianolic acid A, Panax Notoginseng Saponin R1, Ginsenoside Rg1,
Ginsenoside Re, Ginsenoside Rb1, Ginsenoside Rd dihydrotanshinone
I, tanshinone I, cryptotanshinone and tanshinone IIA respectively
at 50 mg/g, 19 mg/g, 30 mg/g, 12 mg/g, 10 mg/g, 20 mg/g, 20 mg/g,
10 mg/g, 40 mg/g, 5 mg/g, 39 mg/g, 10 mg/g, 0.5 mg/g, 1 mg/g, 1
mg/g, 5 mg/g.
99.9 g of the Salvia Miltiorrhiza and Panax Notoginseng extract was
mixed uniformly with 0.1 g of borneol to give the traditional
Chinese medicine.
Preparation of Traditional Chinese Medicine Preparation
Example 10
0.5 g of traditional Chinese medicine composition prepared by any
one method of Examples 1.about.9 was mixed uniformly with 10.5 g of
PEG-6000, molten by heating and delivered to the dropping machine
to acquire medicine drops by means of dropping the medicine
solution into liquid paraffin at 6.about.8.degree. C. Residual
liquid paraffin was removed to give 400 micro drop pills.
Example 11
0.5 g of traditional Chinese medicine composition prepared by any
one method of Examples 1.about.9, 4.5 g of glucose, 0.9 g of sodium
thiosulphate and 1 ml of distilled water were mixed uniformly to
give 500 injectable lyophilized powders by lyophilizing.
Example 12
0.5 g of traditional Chinese medicine composition prepared by any
one method of Examples 1.about.9, 5.5 g of mannitol, 0.9 g of EDTA
calcium disodium and 2 ml of distilled water were mixed uniformly
to give 300 injectable lyophilized powders by lyophilizing.
Example 13
0.5 g of traditional Chinese medicine composition prepared by any
one method of Examples 1.about.9, 50 g of starch and 50 g of
sucrose were mixed uniformly to give the tablets by compression
after granulating.
Example 14
0.5 g of traditional Chinese medicine composition prepared by any
one method of Examples 1.about.9, 50 g of starch and 50 g of
sucrose were mixed uniformly to give the capsules by filling into
capsules.
Preparation of the Micro Drop Pill
Example 15
82.5 g of traditional Chinese medicine composition prepared by the
method of Example 1 and 165 g of PEG-6000 were prepared. (1)
Pre-mixing step: the traditional Chinese medicine composition was
added with water to pre-mix, stirred in the soaking tank at
40.+-.10.degree. C. over 60 min to make the water content of the
composition at 13.0 wt % to give the pre-mixed material for later
use; (2) Melting step: PEG-6000 was firstly input into the melting
tank, pre-molten by heating to 90.degree. C., into which the
pre-mixed material was added and the resultant liquid was mixed by
low-speed homogenization (3200 rpm); after mixing, the
homogenization rate was increased to 5000 rpm to melt for 6 min;
during the melting process, temperature of the liquid was kept at
80.+-.5.degree. C. to give the molten medicine liquid; (3) Dropping
step: aforesaid molten medicine liquid was delivered to the
dripper, the vibration frequency of dripper adjusted to 137 Hz and
temperature of dripper adjusted to 80.degree. C.; the liquid was
delivered to the dripper under pressure (1.8 Bar), from which the
liquid was dropped down by means of vibration; said dropping rate
was matched with the melting rate in step (1); and (4) Condensation
step: the drops were cooled in cooling duct with the
low-temperature inert gas at -115.+-.5.degree. C. to cool the
liquid to form the solid drop pill; (5) Drying step: resultant drop
pill was fluidization dried; until the drop pill reached better
fluidization state, the temperature was increased to 25.degree. C.
to dry for 60 min, continuously increased to 55.degree. C. to dry
for 30 min, and deceased to 30.degree. C. or lower to discharge to
give the intermediate blank drop pill with the water content
controlled in the range of 3.0.about.7.0 wt %; (6) Coating step:
the amount of coating powder was calculated based on coating feed
capacity and formula; Opadry accounting for 4 wt % of the blank
drop pill was used to prepare the 18 wt % coating solution and
stirred for 45 min; inlet air temperature was initially set to
25.degree. C.; after the standard blank drop pills were loaded into
the fluidized bed, the inlet air temperature was increased to
48.degree. C.; until the temperature of the drop pill grew to
38.degree. C., the coating was started; the temperature was kept in
the range of 35.about.45.degree. C. during the coating and
decreased to 30.degree. C. or lower after coating; the pills were
discharged, screened to get the intermediate coating the drop pills
with the coating weight of 3.3.+-.0.7% and the water content in the
range of 3.0.about.7.0 wt %. (7) Loading into capsule and packaging
step: the resultant micro drop pills with the particle size of 1.0
mm.about.2.0 mm were loaded into the capsules; 100% of capsules
were on-line checkweighed with a capsule checkweigher, packaged to
give the final product.
Wherein, during the process of dropping, formation of drop pill was
measured visually by using stroboscopic illumination to perform
real-time monitoring and adjustment. In order to improve the
uniformity and roundness of the drop pills, the step of screening
and regulating might be added.
Example 16
Except that the ratio of traditional Chinese medicine composition
to PEG-6000 was 1:5, the CSMDP was prepared by the method of
Example 15.
Example 17
Except that the ratio of traditional Chinese medicine composition
to PEG-6000 was 5:1, the CSMDP was prepared by the method of
Example 15.
Example 18
Following materials were taken: 82.5 g of traditional Chinese
medicine composition prepared by Example 1 and 165 g of a mixture
of cyclodextrin and agar (1:1). CSMDP was prepared according to the
following method: (1) Melting step: the mixture of cyclodextrin and
agar (1:1) was used as a matrix, charged into the homogenizer with
the traditional Chinese medicine composition to homogenize at 1000
rpm for 1 min to give the material; the material was molten at 3000
rpm for 1 min; during the melting process, the temperature was kept
at 60.degree. C. to obtain the molten medicine liquid; (2) Dropping
step: the molten medicine liquid was delivered to a dripper and
dropped by means of vibration dropping at dripper temperature of
70.degree. C. at a vibration frequency of 50 Hz under a dropping
pressure of 0.5 Bar; said dropping rate was matched with the
melting rate in step (1); and (3) Condensation step: the medicine
drops were cooled with cooling gas rapidly to solidify to obtain
the blank drop pill having a particle size of 0.2 mm; said
temperature of cooling gas was 0.degree. C.
Following materials were taken: 82.5 g of traditional Chinese
medicine composition prepared by Example 1 and 165 g of a mixture
of Arabic gum and lactose (1:1). CSMDP was prepared according to
the following method: (1) Melting step: the mixture of Arabic gum
and lactose (1:1) was used as a matrix, charged into the
homogenizer with the traditional Chinese medicine composition to
homogenize at 5000 rpm for 200 min to give the material; the
material was molten at 10000 rpm for 100 min; during the melting
process, the temperature was kept at 100.degree. C. to obtain the
molten medicine liquid; (2) Dropping step: the molten medicine
liquid was delivered to a dripper and dropped by means of vibration
dropping at dripper temperature of 300.degree. C. at a vibration
frequency of 300 Hz under a dropping pressure of 4.0 Bar; said
dropping rate was matched with the melting rate in step (1); and
(3) Condensation step: the medicine drops were cooled with cooling
gas rapidly to solidify to obtain the blank drop pill having a
particle size of 4.0 mm; said temperature of cooling gas was
-150.degree. C.
Following materials were taken: 82.5 g of traditional Chinese
medicine composition prepared by Example 1 and 165 g of lactitol.
CSMDP was prepared according to the following method: (1) Melting
step: the lactitol was used as a matrix, charged into the
homogenizer with the traditional Chinese medicine composition to
homogenize at 2500 rpm for 100 min to give the material; the
material was molten at 6000 rpm for 50 min; during the melting
process, the temperature was kept at 80.degree. C. to obtain the
molten medicine liquid; (2) Dropping step: the molten medicine
liquid was delivered to a dripper and dropped by means of vibration
dropping at dripper temperature of 150.degree. C. at a vibration
frequency of 150 Hz under a dropping pressure of 2 Bar; said
dropping rate was matched with the melting rate in step (1); and
(3) Condensation step: the medicine drops were cooled with cooling
gas rapidly to solidify to obtain the blank drop pill having a
particle size of 2 mm; said temperature of cooling gas was
-100.degree. C.; (4) Drying step: resultant drop pill was
fluidization dried at 50.degree. C. for 2 hours to give the dried
blank drop pill; (5) Coating step: resultant dried blank drop pills
were coated at 40.degree. C. in fluidized bed to obtain coated drop
pill; said ratio of coating material to the dried blank pills was
1:25; the concentration of said coating solution was 10 wt % and
said coating material was Opadry.
Example 21
Following materials were taken: 82.5 g of traditional Chinese
medicine composition and 165 g of PEG-8000. CSMDP was prepared
according to the following method:
Said traditional Chinese medicine composition powder was added with
water and stirred at 60.degree. C. for 10 min or more to obtain the
pre-mixed traditional Chinese medicine composition. (1) Melting
step: the PEG-8000 and said pre-mixed traditional Chinese medicine
composition were charged into the homogenizer to mix at 2500 rpm
for 100 min to give the material; the material was molten
homogenizedly at 6000 rpm for 50 min; during the melting process,
the temperature was kept at 80.degree. C. to obtain the molten
medicine liquid; (2) Dropping step: the molten medicine liquid was
delivered to a dripper and dropped by means of vibration dropping
at dripper temperature of 150.degree. C. at a vibration frequency
of 150 Hz under a dropping pressure of 2 Bar; said dropping rate
was matched with the melting rate in step (1); and (3) Condensation
step: the medicine drops were cooled with cooling gas rapidly to
solidify to obtain the blank drop pill having a particle size of 2
mm; said temperature of cooling gas was -100.degree. C.; (4) Drying
step: resultant drop pill was fluidization dried at 50.degree. C.
for 2 hours to give the dried blank drop pill; (5) Coating step:
resultant dried blank drop pills were coated at 40.degree. C. in
fluidized bed to obtain coated drop pill; said ratio of coating
material to the dried blank pills was 1:25; the concentration of
said coating solution was 10 wt % and said coating material was
shellac.
Example 22
Following materials were taken: 92 g of traditional Chinese
medicine composition and 270 g of PEG-1000. CSMDP was prepared
according to the following method:
Said traditional Chinese medicine composition powder was added with
water and stirred at 30.degree. C. for 10 min or more to obtain the
pre-mixed traditional Chinese medicine composition. (1) Melting
step: the PEG-1000 and said pre-mixed traditional Chinese medicine
composition were charged into the homogenizer to mix at 2500 rpm
for 100 min to give the material; the material was molten
homogenizedly at 6000 rpm for 20 min; during the melting process,
the temperature was kept at 100.degree. C. to obtain the molten
medicine liquid; (2) Dropping step: the molten medicine liquid was
delivered to a dripper and dropped by means of vibration dropping
at dripper temperature of 70.degree. C. at a vibration frequency of
100 Hz under a dropping pressure of 1.0 Bar; acceleration at 1 G
and dropping rate at 10 Kg/h; said dropping rate was matched with
the melting rate in step (1); and (3) Condensation step: the
medicine drops were cooled with cooling gas rapidly to solidify to
obtain the blank drop pill having a particle size of 2 mm; said
temperature of cooling gas was -80.degree. C.; (4) Drying step:
resultant drop pill was dried by gradient-rising temperature drying
method, fluidized at -20.degree. C., dried at 15.degree. C. for 10
min, 35.degree. C. for 10 min and at 55.degree. C. for 30 min to
give the dried blank drop pill; (5) Coating step: resultant dried
blank pills were coated at 40.degree. C. in fluidized bed to obtain
coated drop pill; said ratio of coating material to the dried blank
pills was 1:25; the concentration of said coating solution was 10
wt % and said coating material was CAP.
Example 23
Following materials were taken: 105 g of traditional Chinese
medicine composition and 35 g of a mixture of PEG-4000: PEG-6000
(1:1). CSMDP was prepared according to the following method:
Said traditional Chinese medicine composition powder was added with
water and stirred at 80.degree. C. for 10 min or more to obtain the
pre-mixed traditional Chinese medicine composition. (1) Melting
step: the mixture of PEG-4000: PEG-6000 (1:1) and said pre-mixed
traditional Chinese medicine composition were charged into the
homogenizer to mix at 2500 rpm for 100 min to give the material;
the material was molten homogenizedly at 6000 rpm for 80 min;
during the melting process, the temperature was kept at 80.degree.
C. to obtain the molten medicine liquid; (2) Dropping step: the
molten medicine liquid was delivered to a dripper and dropped by
means of vibration dropping at dripper temperature of 100.degree.
C. at a vibration frequency of 200 Hz under a dropping pressure of
3.0 Bar; acceleration at 20 G and dropping rate at 40 Kg/h; said
dropping rate was matched with the melting rate in step (1); and
(3) Condensation step: the medicine drops were cooled with cooling
gas rapidly to solidify to obtain the blank drop pill having a
particle size of 2 mm; said temperature of cooling gas was
-120.degree. C.; (4) Drying step: resultant drop pill was dried by
gradient-rising temperature drying method, fluidized at 30.degree.
C., dried at 35.degree. C. for 120 min, at 55.degree. C. for 60 min
and at 100.degree. C. for 60 min to give the dried blank drop pill;
(5) Coating step: resultant dried blank pills were coated at
35.degree. C. in fluidized bed to obtain coated drop pill; said
ratio of coating material to the dried blank pills was 1:25; the
concentration of said coating solution was 10 wt % and said coating
material was methyl acrylate.
Example 24
Following materials were taken: 600 g of traditional Chinese
medicine composition prepared by Example 1, 5 g of borneol and 600
g of xylitol as drop pill matrix. (1) Melting step: the xylitol was
firstly charged into the melting tank and heated to 90.degree. C.
to pre-melt, into which said pre-mixed traditional Chinese medicine
composition was charged to mix to give the molten medicine liquid;
(2) Dropping step: under pressure the molten medicine liquid was
delivered to a dripper that was heated and preserved by steam
jacket; at dripper temperature of 40.degree. C. and a vibration
frequency of 50 Hz, said molten medicine liquid flowed into the
dripper and dropped from the bottom; (3) Condensation step: the
medicine drops were cooled in a cooling duct with low-temperature
inert gas to solidify to obtain the solid drop pill; said cooling
temperature was -20.degree. C.; (4) Drying & coating step:
resultant solid drop pill was fluidization dried and drug-loading
coated to give the coated micro drop pill with the particle size of
0.2 mm.about.1.0 mm; said drying temperature was 75.degree. C.; and
(5) Packaging step: said micro drop pills with the particle size of
0.2 mm.about.1.0 mm were loaded into the capsules; 100% of capsules
were on-line checkweighed with a capsule checkweigher and packaged
to give the final product.
Wherein, during the process of dropping, formation of drop pill was
measured visually by using stroboscopic illumination to perform
real-time monitoring and adjustment. In order to improve the
uniformity and roundness of the drop pills, the step of screening
and regulating might be added.
Example 25
Following materials were taken: 600 g of traditional Chinese
medicine composition prepared by Example 1, 5 g of borneol and 3000
g of a mixture of PEG-6000 and PEG-4000 as drop pill matrix. (1)
Melting step: the mixture of PEG-6000 and PEG-4000 was firstly
charged into the melting tank and pre-molten by heating to
120.degree. C., into which said pre-mixed traditional Chinese
medicine composition was charged to well mix to give the molten
medicine liquid; (2) Dropping step: under pressure the molten
medicine liquid was delivered to a dripper that was heated and
preserved by steam jacket; at dripper temperature of 80.degree. C.
and a vibration frequency of 20 Hz, said molten medicine liquid
flowed into the dripper and dropped from the bottom; (3)
Condensation step: the medicine drops were cooled in a cooling duct
with low-temperature inert gas to solidify to obtain the solid drop
pill; said cooling temperature was -80.degree. C.; (4) Drying &
coating step: resultant solid drop pill was fluidization dried and
drug-loading coated to give the coated micro drop pill with the
particle size of 0.5 mm.about.1.0 mm; said drying temperature was
150.degree. C.; and (5) Packaging step: said micro drop pills were
loaded into the capsules; 100% of capsules were on-line
checkweighed with a capsule checkweigher and packaged to give the
final product.
Wherein, during the process of dropping, formation of drop pill was
measured visually by using stroboscopic illumination to perform
real-time monitoring and adjustment. In order to improve the
uniformity and roundness of the drop pills, the step of screening
and regulating might be added.
Example 26
Following materials were taken: 600 g of traditional Chinese
medicine composition prepared by Example 1, 5 g of borneol and 120
g of PEG-1000 as drop pill matrix. (1) Melting step: the PEG-1000
was firstly charged into the melting tank and pre-molten by heating
to 40.degree. C., into which said pre-mixed traditional Chinese
medicine composition was charged to well mix to give the molten
medicine liquid; (2) Dropping step: under pressure the molten
medicine liquid was delivered to a dripper that was heated and
preserved by steam jacket; at dripper temperature of
40.about.60.degree. C. and a vibration frequency of 200 Hz, said
molten medicine liquid flowed into the dripper and dropped from the
bottom; (3) Condensation step: the medicine drops were cooled in a
cooling duct with low-temperature inert gas to solidify to obtain
the solid drop pill; said cooling temperature was -100.degree. C.;
(4) Drying & coating step: resultant solid drop pill was
fluidization dried and drug-loading coated, fluidized at 20.degree.
C., dried at 25.degree. C. for 60 min, at 45.degree. C. for 30 min
and at 55.degree. C. for 30 min to give the coated micro drop pill
with the particle size of 3.0 mm.about.4.0 mm; and (5) Packaging
step: said micro drop pills were loaded into the capsules; 100% of
capsules were on-line checkweighed with a capsule checkweigher and
packaged to give the final product.
Wherein, during the process of dropping, formation of drop pill was
measured visually by using stroboscopic illumination to perform
real-time monitoring and adjustment. In order to improve the
uniformity and roundness of the drop pills, the step of screening
and regulating might be added.
Example 27
Following materials were taken: 600 g of traditional Chinese
medicine composition prepared by Example 1, 5 g of borneol and 3000
g of a mixture of PEG-6000 and PEG-4000 as drop pill matrix. (1)
Melting step: the mixture of PEG-6000 and PEG-4000 was firstly
charged into the melting tank and pre-molten by heating to
120.degree. C., into which said pre-mixed traditional Chinese
medicine composition was charged and poured into the homogenizer to
mix at 1000 rpm for 1 min and melt at 3000 rpm for 1 min, during
the melting process, the temperature was kept at 60.degree. C. to
obtain the molten medicine liquid; (2) Dropping step: under
pressure the molten medicine liquid was delivered to a dripper that
was heated and preserved by steam jacket; at dripper temperature of
70.degree. C., a vibration frequency of 50 Hz and dropping pressure
of 0.5 Bar, said molten medicine liquid flowed into the dripper and
dropped from the bottom; (3) Condensation step: the medicine drops
were cooled in a cooling duct with low-temperature inert gas to
solidify to obtain the solid drop pill; said cooling temperature
was 0.degree. C.; (4) Drying & coating step: resultant solid
drop pill was fluidization dried and drug-loading coated to give
the coated micro drop pill with the particle size of 0.2 mm; said
drying temperature was 150.degree. C.; and (5) Packaging step: said
micro drop pills were loaded into the capsules; 100% of capsules
were on-line checkweighed with a capsule checkweigher and packaged
to give the final product.
Example 28
Following materials were taken: 600 g of traditional Chinese
medicine composition prepared by Example 1, 5 g of borneol and 1800
g of PEG-6000 as drop pill matrix. (1) Melting step: the PEG-6000
was firstly charged into the melting tank and pre-molten by heating
to 120.degree. C., into which said pre-mixed traditional Chinese
medicine composition was charged and poured into the homogenizer to
mix at 5000 rpm for 200 min and melt at 10000 rpm for 1 min, during
the melting process, the temperature was kept at 100.degree. C. to
obtain the molten medicine liquid; (2) Dropping step: under
pressure the molten medicine liquid was delivered to a dripper that
was heated and preserved by steam jacket; at dripper temperature of
300.degree. C., a vibration frequency of 300 Hz and dropping
pressure of 4.0 Bar, said molten medicine liquid flowed into the
dripper and dropped from the bottom; (3) Condensation step: the
medicine drops were cooled in a cooling duct with low-temperature
inert gas to solidify to obtain the solid drop pill; said cooling
temperature was -150.degree. C.; (4) Drying & coating step:
resultant solid drop pill was fluidization dried and drug-loading
coated to give the coated micro drop pill with the particle size of
4.0 mm; said drying temperature was 150.degree. C.; and (5)
Packaging step: said micro drop pills were loaded into the
capsules; 100% of capsules were on-line checkweighed with a capsule
checkweigher and packaged to give the final product.
Example 29
Following materials were taken: 600 g of traditional Chinese
medicine composition prepared by Example 1, 5 g of borneol and 2400
g of PEG-4000 as drop pill matrix. (1) Melting step: the PEG-4000
was firstly charged into the melting tank and pre-molten by heating
to 120.degree. C., into which said pre-mixed traditional Chinese
medicine composition was charged, homogenized at 3000 rpm for 10
min and molten homogenizedly at 4000 rpm for 5 min, during the
melting process, the temperature was kept at 70.about.90.degree. C.
to obtain the molten medicine liquid; (2) Dropping step: under
pressure the molten medicine liquid was delivered to a dripper that
was heated and preserved by steam jacket; at dripper temperature of
70.degree. C., a vibration frequency of 90 Hz and dropping pressure
of 1.0 Bar, said molten medicine liquid flowed into the dripper and
dropped from the bottom; (3) Condensation step: the medicine drops
were cooled in a cooling duct with low-temperature inert gas to
solidify to obtain the solid drop pill; said cooling temperature
was -140.degree. C.; and (4) Drying step: resultant solid drop pill
was fluidization dried to give the micro drop pill with the
particle size of 1.0 mm; said drying temperature was 150.degree.
C.
Following materials were taken: 600 g of traditional Chinese
medicine composition prepared by Example 1, 5 g of borneol and 2400
g of PEG-4000 as drop pill matrix. (1) Melting step: the PEG-4000
was firstly charged into the melting tank and pre-molten by heating
to 120.degree. C., into which said pre-mixed traditional Chinese
medicine composition was charged, homogenized at 4000 rpm for 60
min and molten homogenizedly at 9000 rpm for 30 min, during the
metling melting process, the temperature was kept at 90.degree. C.
to obtain the molten medicine liquid; (2) Dropping step: under
pressure the molten medicine liquid was delivered to a dripper that
was heated and preserved by steam jacket; at dripper temperature of
100.degree. C., a vibration frequency of 200 Hz and dropping
pressure of 3.0 Bar, said molten medicine liquid flowed into the
dripper and dropped from the bottom; (3) Condensation step: the
medicine drops were cooled in a cooling duct with low-temperature
inert gas to solidify to obtain the solid drop pill; said cooling
temperature was -140.degree. C.; and (4) Drying step: resultant
solid drop pill was fluidization dried to give the micro drop pill
with the particle size of 2.0 mm; said drying temperature was
150.degree. C.
Example 31
Following materials were taken: 600 g of traditional Chinese
medicine composition prepared by Example 1, 5 g of borneol and 2000
g of PEG-6000 as drop pill matrix. (1) Melting step: the PEG-6000
was firstly charged into the melting tank and pre-molten by heating
to 90.degree. C., into which said pre-mixed traditional Chinese
medicine composition was charged to well mix to give the molten
medicine liquid; (2) Dropping step: under pressure the molten
medicine liquid was delivered to a dripper that was heated and
preserved by steam jacket; at dripper temperature of 80.degree. C.
and a vibration frequency of 50 Hz, said molten medicine liquid
flowed into the dripper and dropped from the bottom; (3)
Condensation step: the medicine drops were cooled in a cooling duct
with low-temperature inert gas to solidify to obtain the solid drop
pill; said cooling temperature was -20.degree. C.; (4) Drying &
coating step: resultant solid drop pill was fluidization dried and
drug-loading coated give the coated micro drop pill with the
particle size of 1.0 mm.about.2.0 mm; said drying temperature was
75.degree. C.; and (5) Packaging step: said micro drop pills were
loaded into the capsules; 100% of capsules were on-line
checkweighed with a capsule checkweigher and packaged to give the
final product.
Wherein, during the process of dropping, formation of drop pill was
measured visually by using stroboscopic illumination to perform
real-time monitoring and adjustment. In order to improve the
uniformity and roundness of the drop pills, the step of screening
and regulating might be added.
As found in the study by the inventors, compared with existing
CSDP, the CSMDP prepared by the methods disclosed in the Examples
15.about.31 had the merits of good efficacy, high bioavailability,
reduced administration dose and good compliance to the
patients.
Preparation of Salvianolic Acid T
Example 32
Salvia Miltiorrhiza was transferred to an herbal decocting pot,
into which 6 times of 0.3% (w/v) sodium bicarbonate aqueous
solution based on the amount of Salvia Miltiorrhiza was added,
decocted for 2.5 h and filtered to give the filtrate. The filtrate
was concentrated to obtain the aqueous extract with relative
density of 1.22 (80.degree. C.).
The aqueous extract was added with 95% (v/v) ethanol to make the
final ethanol content as 60% (v/v) (25.degree. C.) and allowed to
stand still for 24 h to give the supernatant. The supernatant was
concentrated under reduced pressure to obtain the
ethanol-precipitated extract with a relative density of 1.32
(60.degree. C.).
The ethanol-precipitated extract was dissolved with water, passed
through AB-8 macroporous resin column and eluted with aqueous
hydrochloric acid solution (pH=3.0) until the eluent was nearly
colorless. Later, 5 times of 95% (v/v) ethanol based on the column
volume was used to elute the column and the eluent was concentrated
to give the extract with no smell of alcohol.
The extract obtained from previous step was dissolved with mobile
phase (acetonitrile:water:formic acid=15:85:1 by volume) and
purified with NOVASEP LC80-600 dynamic axial high-pressure
preparative LC. C18 reverse-phase chromatographic column (10 .mu.m,
YMC Inc.) was used as stationary phase to carry out the isocratic
elution with the mobile phase of acetonitrile:water:formic
acid=15:85:1 by volume. The flow rate was at 300 mL/min and
detective wavelength at 280 nm. The process of elution was
monitored by using HPLC to collect the fraction between
21.2.about.24.0 min and concentrate to dry with the rotary
evaporator to obtain salvianolic acid T.
Afore-obtained salvianolic acid T was dissolved with mobile phase
(acetonitrile:water:formic acid=17:83:1 by volume) and Waters Prep
400 preparative LC was used to carry out chiral isomer separation.
The chromatographic column was CHIRALCEL.RTM. OD-RH reverse-phase
chiral column (250.times.20 mm, 5 .mu.m) and the mobile phase of
acetonitrile:water:formic acid=17:83:1 by volume was used to
perform isocratic elution. The flow rate was at 25 mL/min and
detective wavelength at 280 nm. The process of elution was
monitored by using HPLC to collect the fraction of (S)-salvianolic
acid T between retention time of 19.5.about.21.1 min and
(R)-salvianolic acid T between retention time of 23.9.about.25.3
min. The eluent was concentrated with rotary evaporator at
30.degree. C. and lyophilized to obtain the pure product of (S)-
and (R)-salvianolic acid T.
By using a high-resolution mass spectrometry, a quasi-molecular ion
peak of (S)-salvianolic acid T was at m/z 537.1033 and
(R)-salvianolic acid T at m/z 537.1032.
NMR data assignments for (S)-salvianolic acid T and (R)-salvianolic
acid T were seen in the following tables.
TABLE-US-00006 TABLE 6 .sup.1H (DMSO, J Hz) data assignment for the
(R)-salvianolic acid T .sup.1H-.sup.1H No. .delta..sub.H .DELTA.c
COSY HMBC 1 -- 123.7 H-5, H-8 2 -- 126.4 H-6, H-7, H-7'' 3 -- 142.9
H-5 4 -- 147.7 H-5, H-6 5 6.85 (1H, d, 8.5 Hz) 115.0 H-6 6 7.31
(1H, d, 8.5 Hz) 118.4 H-5 H-7 7 7.41 (1H, d, 15.5 Hz) 143.7 H-8 H-6
8 6.27 (1H, d, 15.5 Hz) 113.9 H-7 H-7 9 -- 166.0 H-7, H-8, H-8' 1'
-- 127.1 H-2', H-5', H-8', H-7' 2' 6.62 (1H, s) 116.5 H-6' H-6' 3'
-- 143.9 H-2', H-5' 4' -- 144.8 H-2', H-5', H-6' 5' 6.63 (1H, d,
8.0 Hz) 115.5 H-6' H-6' 6' 6.47 (1H, d, 8.0 Hz) 120.0 H-2', 5'
H-2', H-5' 7' 2.89 (2H, ddd, 14.0, 36.0 H-8' H-2', H-5', H-6', 8.0,
4.5 Hz) H-8' 8' 4.93 (1H, dd, 8.0, 4.5 72.8 H-7' H-7' Hz) 9' --
170.6 H-7', H-8' 1'' -- 126.0 H-2'' 2'' 6.44 (1H, d, 2.0 Hz) 117.3
H-6'' H-6'', H-7'' 3'' -- 144.8 H-2'', H-5'' 4'' -- 147.2 H-2'',
H-5'', H-6'' 5'' 6.55 (1H, d, 8.5 Hz) 115.3 H-6'' 6'' 6.43 (1H, dd,
8.5, 2.0 122.9 H-2'', 5'' H-2'', H-7'' Hz) 7'' 7.69 (1H, s) 141.1
H-6'' 8'' -- 123.4 H-7'' 9'' -- 168.4 H-7''
TABLE-US-00007 TABLE 7 .sup.1H (DMSO, J Hz) data assignment for the
(S)-salvianolic acid T .sup.1H-.sup.1H No. .delta..sub.H .DELTA.c
COSY HMBC 1 -- 123.8 H-5, H-8 2 -- 126.3 H-6, H-7, H-7'' 3 -- 142.9
H-5 4 -- 147.7 H-5, H-6 5 6.85 (1H, d, 8.5 Hz) 115.0 H-6 6 7.29
(1H, d, 8.5 Hz) 118.4 H-5 H-7 7 7.41 (1H, d, 15.5 Hz) 143.7 H-8 H-6
8 6.27 (1H, d, 15.5 Hz) 114.0 H-7 H-7 9 -- 165.9 H-7, H-8, H-8' 1'
-- 127.2 H-2', H-5', H-8', H-7' 2' 6.62 (1H, s) 116.5 H-6' H-6',
H-7' 3' -- 143.9 H-2', H-5', H-6' 4' -- 144.9 H-2', H-5' 5' 6.63
(1H, d, 8.0 Hz) 115.5 H-6' 6' 6.45 (1H, d, 8.0 Hz) 120.1 H-2', 5'
H-2', H-5', H-7' 7' 2.87 (2H, ddd, 14.0, 36.1 H-8' H-2', H-5',
H-6', 8.0, 4.0 Hz) H-8' 8' 4.92 (1H, dd, 8.0, 4.0 72.9 H-7' H-7'
Hz) 9' -- 170.6 H-7', H-8' 1'' -- 126.0 H-5'' 2'' 6.43 (1H, d, 2.0
Hz) 117.3 H-6'' H-6'', H-7'' 3'' -- 144.8 H-2'', H-5'' 4'' -- 147.2
H-2'', H-5'', H-6'' 5'' 6.55 (1H, d, 9.0 Hz) 115.3 H-6'' 6'' 6.43
(1H, dd, 8.5, 2.0 122.9 H-2'', 5'' H-2'', H-7'' Hz) 7'' 7.69 (1H,
s) 141.1 H-2'', H-6'' 8'' -- 123.3 9'' -- 168.4 H-7''
In order to better prove the merits of the present invention, the
trial was presented as follows:
Trial Example 1
1. Materials
2. Animals
SD male rats, weighing 200 g, were purchased from Beijing
Weitonglihua Experimental Animal Co., Ltd, with certification No.:
SCXK (JING) 2007-0001.
Rabbits, male, weighing 1.7.about.2.0 kg, were purchased from
Qinglongshan Animal Reproduction Plant, Jiangning Country, Nanjing
with certification No.: SCXK (SU) 2007-2008.
3. Drugs and Reagents
The Salvia Miltiorrhiza and Panax Notoginseng extracts were divided
into two types, which were prepared by the method of Example 1,
Extract A (with borneol) and Extract B (without borneol). Chloral
hydrate and triphenyl tetrazolium chloride (TTC) were used.
Aspirin enteric-coated tablet was purchased from Baijingyu
Pharmaceutical Inc, Nangjing. Batch number was 111001.
Arachidonic acid (AA) was provided by Sigma Inc in specification of
10 mg/bottle, and batch number was 1001126252.
Monosodium adenosine diphosphate (ADP) was provided by Shanghai
Boao Bio-tech Inc (Imported). Batch number was 990527.
Collagen was provided by Sigma Inc. in specification of 10
mg/bottle, and batch number was 1001162038.
4. Protocol
2.1 Acute Myocardial Infarction Experiment in Rats
32 rats were randomly divided into groups according to the body
weight: the blank group, model group, group A (with borneol) and
group B (without borneol); 8 rats in each group.
After grouping, all animals were administrated intragastrically for
1 week, which was seen in Table 8. On 8.sup.th day, the animals
were anesthetized by intraperitoneal injection of 10% chloral
hydrate (3 ml/kg) and fixed on a small plate in a supine position.
Conductors were inserted under the skin of right forelimb and both
hind limbs, which was connected with the MedLab-U/8c bio-signal
collecting-processing system to record the ECG of rats. Hair on
front wall of left chest was clipped. Oral tracheal cannula was
performed and the animal respirator was connected at respiratory
frequency of 80 breaths/min, tidal volume 3 ml/100 g and I:E=1:2.
Chest on left front chest lateral side was incised to cut 3.sup.rd
rib and the pericardium carefully lifted with forceps to tear
apart. Left coronary vein trunk pass between the lower edge of left
atrial appendage and pulmonary artery cone was observed in most of
animals, accompanied with LAD. Medical suture (4-0) was used to
ligate LAD and a small amount of myocardial tissue 1.about.2 mm
from the low edge of left atrial appendage inside the
interventricular sulcus in the vicinity of left coronary vein
trunk. Chest was closed layer by layer. The tracheal tube was
detubated until the respiration was recovered in rats.
Testing index: after 4 h ligation, the animals were euthanized. The
hearts were taken out and washed with 0.9% sodium chloride
injection to absorb the water. Along the coronary sulcus, the
atrium was cut to weigh wet ventricular mass. The heart was sliced
into 1 mm thickness of myocardial sections in parallel from the
apex to the base portion along ventricular ditch. Obtained
myocardium was placed in TTC colorant to dye for 15 min on
37.degree. C. thermal water bath. Normal myocardium was dyed red
and infarcted area white. Wet mass in each section of infarcted
area was weighed to calculate the myocardial infarction rate
(MIR).
TABLE-US-00008 TABLE 8 grouping and administrating Groups dosage
Dose Administration time Sham operation 1 ml/100 g 7 d Model group
1 ml/100 g 7 d Group A 83.7 mg/kg 1 ml/100 g 7 d Group B 83.7 mg/kg
1 ml/100 g 7 d
2.2 Platelet Aggregation Rate Trial in Rabbits
The rabbits were randomly grouped into 4 groups: the model group
was given with distilled water, the aspirin group (60 mg/ml),
Extract A groups of low dose and high dose at 42 and 84 mg/kg
(respectively 1.about.2 times of clinic equivalent dosage),
intragastrically administrated, once a day for 7 consecutive days.
The volume of medicine administrated was 1 ml/kg body weight. 60
min after intragastric administration on 7.sup.th day, the animals
were anesthetized locally, blooded through carotid artery,
anticoagulated with sodium citrate (3.8%) 1:9 and centrifugated at
1000 r/min for 10 min. Platelet-rich plasma (PRP) was taken and the
remain centrifugated at 3000 r/min to take platelet-poor plasma
(PPP. Aggregation was induced by ADP (final concentration 3
.mu.g/ml), AA (final concentration 80 .mu.g/ml) and collagen (5
m/ml). STEELIEX platelet aggregation & coagulation factor
analyzer was used to measure the maximum platelet aggregation rate
and to calculate inhibition rate according to following
formula.
.times. ##EQU00001## Results
3.1 Experimental Results of Myocardial Infarction in Rats
The results were in Table 9. 7 days after pre-administration,
compared with the model group (0.122.+-.0.018 g), the weights of
myocardial infarction in group A and group B (0.070.+-.0.020 g,
0.089.+-.0.021 g) were decreased obviously, having statistical
significance. According to the results of inter-group comparison,
the ratio of myocardial infarction in group A was much less than
that in group B, having significant difference between two groups
(p<0.05).
TABLE-US-00009 TABLE 9 effect of Salvia Miltiorrhiza and Panax
Notoginseng extract on weight of myocardial infarction in rabbits
(n = 6) Average wet Average wet Wet weight of Dose weight weight of
infarction/wet (mg/ of whole myocardial weight of whole Group kg)
heart (g) infarction (g) heart .times. 100% (%) Blank 0.896 .+-.
0.034 0 0.00 .+-. 0.00 group Model 0.932 .+-. 0.085 0.122 .+-.
0.018 13.09 .+-. 1.58 group Group A 83.7 0.869 .+-. 0.042 0.070
.+-. 0.020* 8.05 .+-. 1.79* Group B 83.7 0.930 .+-. 0.099 0.089
.+-. 0.021*# 9.57 .+-. 1.92*# Note: compared with the model group,
*p < 0.05; compared with Group A, #p < 0.05
3.2 Effect on Platelet Aggregation Rate in Rabbits
As shown in Table 10, Extract A was proven to have inhibitory
effect on ADP-induced platelet aggregation in rabbits, which,
compared with the blank group, had a significant difference.
Compared with the aspirin group, no significant difference was
found in the group A in inhibiting ADP-induced platelet
aggregation.
TABLE-US-00010 TABLE 10 effect of Extract A on ADP-induced platelet
aggregation in rabbits (x .+-. s, n = 8) Platelet Dose aggregation
Group (mg/kg) rate (%) Blank group 0 31.02 .+-. 5.30 Aspirin group
60 18.96 .+-. 4.11** Group A-low dose 42 25.43 .+-. 4.56* Group
A-high dose 84 21.72 .+-. 4.32** *P < 0.05, **P < 0.01,
compared with the blank group.
As shown in Table 11, Extract A was proven to have inhibitory
effect on AA-induced platelet aggregation in rabbits, which,
compared with the blank group, had a significant difference.
Compared with the aspirin group, no significant difference was
found in the group A in inhibiting AA-induced platelet
aggregation.
TABLE-US-00011 TABLE 11 effect of Extract A on AA-induced platelet
aggregation in rabbits (x .+-. s, n = 8) Platelet Dose aggregation
Group (mg/kg) rate (%) Blank group 0 10.01 .+-. 2.21 Aspirin group
60 6.13 .+-. 2.03** Group A-low dose 42 8.02 .+-. 3.32 Group A-high
dose 84 6.32 .+-. 2.21** *P < 0.05, **P < 0.01, compared with
the model group.
As shown in Table 12, Extract A was proven to have inhibitory
effect on collegan-induced platelet aggregation in rabbits, which,
compared with the blank group, had a significant difference.
Compared with the aspirin group, no significant difference was
found in the group A in inhibiting collagen-induced platelet
aggregation.
TABLE-US-00012 TABLE 12 effect of Extract A on collagen-induced
platelet aggregation in rabbits (x .+-. s, n = 8) Platelet Dose
aggregation Group (mg/kg) rate (%) Blank group 0 15.90 .+-. 4.21
Aspirin group 60 6.23 .+-. 2.41** Group A-low dose 42 10.55 .+-.
3.23* Group A-high dose 84 6.47 .+-. 2.32** *P < 0.05, **P <
0.01, compared with the model group.
As shown in the results, administration of Salvia Miltiorrhiza and
Panax Notoginseng extract for 7 consecutive days could take effect
of antimyocardial infarction in ligated rats.
In Group A, the Salvia Miltiorrhiza and Panax Notoginseng extract
with Borneol was administrated for 7 consecutive days. Obviously,
the myocardial infarction rate was less than that in Group B
(without Borneol) and had significantly inhibitory effect on ADP,
AA or collagen induced platelet aggregation in rabbits.
The preliminary conclusion showed that addition of borneol might
strengthen the efficacy of anti-myocardial infarction.
Trial Example 2
Comparative Study on Effect of Acute Myocardial Infarction in Rats
Between Two Kinds of CSDPs
1. Animals
SD male rats, weighing 340.about.360 g, were purchased from Beijing
Weitonglihua Experimental Animal Co., Ltd, with certification No.:
SCXK (JING) 2007-0001.
2. Drugs, Reagents and Apparatus
CSMDP was prepared by the method of Preparative Example 15 of
CSMDP.
CSDP, used as compared drug, was commercially available in China,
prepared by Tianjin Tasly Pharmaceutical Co., Ltd.
Anesthesia was performed by chloral hydrate and triphenyl
tetrazolium chloride (TTC).
Apparatus: MedLab-U/8c bio-signal collecting-processing system,
purchased from Nanjin Meiyi Inc.
3. Protocol
Grouping: rats were randomly divided into groups according to the
body weight: S group (the sham operation group), M group (the model
group), Y group (the positive group, Metoprolol Tartrate, Lot No.
1201039), F group (the CSMDP group in the present invention) and G
group (the CSDP group commercially available in China, batch
number: 2011L16); 10 rats in each group.
Modeling and Administrating Method:
After grouping, the animals were administrated intragastrically for
7 days, which was seen in Table 13. On 8.sup.th day, the rats were
anesthetized by intraperitoneal injection of 10% chloral hydrate (3
ml/kg) and fixed on a small wood plate in a supine position. Pins
were inserted under the skin of right forelimb and both hind limbs,
which was connected with the MedLab-U/8c bio-signal
collecting-processing system to record the ECG of rats. Hair on
front wall of left chest was clipped. Oral tracheal cannula was
performed and the animal respirator was connected at respiratory
frequency of 80 breaths/min, tidal volume 3 ml/100 g and I:E=1:2.
Chest on left front chest lateral side was incised to cut 3.sup.rd
rib and the pericardium carefully lifted with forceps to tear
apart. Left coronary vein trunk pass between the lower edge of left
atrial appendage and pulmonary artery cone was observed in most of
animals, accompanied with LAD. Medical suture (4-0) was used to
ligate LAD and a small amount of myocardial tissue 1.about.2 mm
from the low edge of left atrial appendage inside the
interventricular sulcus in the vicinity of left coronary vein
trunk. The rats with elevated J point by 0.1 mV in ECG and pale
LVAW (left ventricular anterior wall) represented the successful
modeling. Chest was closed layer by layer. The tracheal tube was
detubated until the respiration was recovered in rats. ECG was
recorded continuously for 4 hours. Rats were anesthetized, heart
taken out, sliced and dyed to calculate myocardial infarction rate
(MIR). The serum was for later use. MIR (%)=wet weight of
infarction area/wet weight of whole heart.times.100%
TABLE-US-00013 TABLE 13 Grouping and administration Concentrate
Pre-admin- Group (mg/kg) Dose istration time S group 110 1 ml/100 g
7 d M group 223 1 ml/100 g 7 d Y group 4.5 1 ml/100 g 7 d G group
115 1 ml/100 g 7 d F group 84 1 ml/100 g 7 d
Results
4.1 Effect on MIR
The results were in Table 14. As shown in Table 14, 7 days after
pre-administration, MIR in M group was significantly higher than
that in S group, suggesting the successful modeling. MIR in G group
and F group were respectively 3.38% and 3.32%, significantly lower
than that in M group (5.07%), having a significant difference
(p<0.01). It was indicated that both samples had a certain
effect against acute myocardial infarction. However, there was no
significantly statistical difference (p>0.05) in comparison to
those in G group and F group.
TABLE-US-00014 TABLE 14 effect of CSDP in each group on MIR Average
wet Average wet weight of whole weight of infar- Group N heart (g)
ction area (g) MIR (%) S group 8 0.8254 .+-. 0.0294 0.0000 .+-.
0.0000 0.00 .+-. 0.00 M group 10 0.8207 .+-. 0.0447 0.0414 .+-.
0.0051 5.07 .+-. 0.75 Y group 9 0.8783 .+-. 0.0571 0.0233 .+-.
0.0038 2.65 .+-. 0.33* G group 10 0.8493 .+-. 0.0641 0.0288 .+-.
0.0052 3.38 .+-. 0.49*# F group 10 0.8242 .+-. 0.0651 0.0257 .+-.
0.0044 3.12 .+-. 0.67*# Note: compared with the M group, *p <
0.01; compared with the Y group, #p < 0.01
4.2 Effect on Heart Rate in Rats with Myocardial Infarction
As shown in Table 15, the descending order of heart rate in each
group was F group, G group, M group, Y group and S group within
observation time and 0.about.1 hour after ligation. 1 hour later,
the heart rate in each group was decreased. Within observation
time, the variation of heart rate in Y group and S group was
relatively stable. There was no significant difference on heart
rate in rats among groups.
TABLE-US-00015 TABLE 15 effect of CSDP in each group on heart rate
(beat/mm) Group N 0 s 5 s 10 s S group 8 390 .+-. 50 390 .+-. 52
400 .+-. 51 M group 10 416 .+-. 83 447 .+-. 72 436 .+-. 67 Y group
9 377 .+-. 48 423 .+-. 39 419 .+-. 41 G group 10 431 .+-. 43 452
.+-. 21 444 .+-. 24 F group 10 448 .+-. 26 496 .+-. 37 464 .+-. 32
Group 5 min 10 min 30 min 1 h S group 407 .+-. 43 401 .+-. 57 386
.+-. 69 394 .+-. 58 M group 444 .+-. 43 423 .+-. 39 423 .+-. 32 399
.+-. 31 Y group 424 .+-. 29 431 .+-. 17 413 .+-. 34 421 .+-. 47 G
group 445 .+-. 29 424 .+-. 27 422 .+-. 25 397 .+-. 25 F group 471
.+-. 38 465 .+-. 33 424 .+-. 41 414 .+-. 44 Group 2 h 3 h 4 h S
group 417 .+-. 44 364 .+-. 42 358 .+-. 36 M group 361 .+-. 45 363
.+-. 46 336 .+-. 59 Y group 416 .+-. 33 380 .+-. 66 395 .+-. 52 G
group 392 .+-. 40 347 .+-. 39 331 .+-. 38 F group 391 .+-. 50 379
.+-. 58 363 .+-. 49
5. Conclusion
At dose of this study, the medicines in each group were proven to
have a certain effect against myocardial infarction in ligature
rats on coronary artery; especially the CSMDP of the present
invention (84 mg/kg) had MIR of 3.12.+-.0.67%, having a similar
efficacy of MIR (3.38.+-.0.49%) with the commercially available
CSDP (115 mg/kg). Obviously, the CSMDP at a dose of 84 mg/kg
reached the same effect with the commercially available CSDP at 115
mg/kg. The CSMDP had a better efficacy than the commercially
available CSDP, having the merits of high bioavailability, reduced
administration dose and good compliance to the patients.
* * * * *