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.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is

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 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˜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 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.

Claims

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˜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˜90 parts and panax notoginseng 10˜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˜4.2):(1.0˜1.3):(1.5˜1.9):(0.5˜0.7):(0.5˜0.9):(1.1˜1.6):(0.7˜1.2):(0.5˜0.9):(1.9˜2.5):(0.2˜0.4):(1.6˜2.2):(0.2˜0.6):(0.03˜0.04):(0.07˜0.08):(0.05˜0.06):(0.26˜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° 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° 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° 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° 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° 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° 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° C., for 1-4 hours to obtain a blank drop pill.

15. The preparation method according to claim 11 14, 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° C.; wherein the concentration of coating liquid is at 5-25 wt %, coating material is selected from shellac, CAP (cellulose acetate phthalate), methyl acrylate, or 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° 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˜5000 rpm for 10˜60 min and melting homogeneously at 4000˜9000 rpm for 5˜30 min, during the melting process, the temperature is kept at 70˜90° C.; in step (2), the temperature of the dripper is at 70˜100° C.; the vibration frequency is at 50˜300 Hz; the acceleration is at 3.5˜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˜−150° C.

19. The preparation method according to claim 18, wherein in step (1), the ratio of the medicine to the matrix is 1:(1˜3) by weight, mixing homogeneously 3000˜4000 rpm for 10˜30 min and melting homogeneously at 4000˜6000 rpm for 6˜30 min, and during the melting process, the temperature is kept at 75˜85° C.,

in step (2) the temperature of the dripper is at 75˜85° C., the vibration frequency is at 100˜200 Hz the acceleration is at 3.5˜4.5 G, the dropping pressure is at 1.0˜3.0 Bar, and the dropping rate is 10˜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˜−120° C.; the particle size is 1.0 mm˜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˜30° C., drying at 15˜35° C. for 10˜120 min, drying at 35˜55° C. for 10˜60 min, drying at 55˜100° C. for 0˜60 min.

21. The preparation method according to claim 11, wherein said method additionally comprises a step (4) of drying: fluidizing at 0˜20° C., drying at 25° C. for 60 min, drying at 45° C. for 30 min, drying at 55° C. for 0˜30 min.

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° 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° 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° 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° 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° 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° C. to dry for 60 min, continuously increased to 55° C. to dry for 30 min, and deceased to 30° C. or lower to discharge to give the intermediate blank drop pill with the water content controlled in the range of 3.0˜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° C.; after the standard blank drop pills are loaded into the fluidized bed, the inlet air temperature is increased to 48° C.; until the temperature of the drop pill grew to 38° C., the coating is started; the temperature is kept in the range of 35˜45° C. during the coating and decreased to 30° 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˜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.

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.

24. A pharmaceutical preparation comprising the Chinese medicine composition according to claim 4 and pharmaceutically acceptable carriers.