CN1299741C - Chinese traditional medicine preparation for treating coronary heart disease and process for preparing the same - Google Patents

Abstract

The present invention discloses a preparation of traditional Chinese medicine for treating coronary heart disease and a preparing method thereof. The preparation has the raw materials by the proportion (following weight parts): 5 to 35 parts of hawthorn fruit, 5 to 25 parts of kudzuvine root, 5 to 35 parts of Chinese yam, 5 to 30 parts of white peony root and 5 to 35 parts of glabrous greenbrier rhizome. The preparation of traditional Chinese medicine has good effects on enhancing coronary blood flow, improving the microcirculation of the heart and brain, resisting the formation of atherosclerotic plaque and controlling angina pectoris and myocardial infarction, but does not have toxic and side effects.

Description

A kind of Chinese medicine preparation for the treatment of coronary heart disease and preparation method thereof

Technical field

The present invention relates to a kind of Chinese medicine preparation, particularly a kind of Chinese medicine preparation for the treatment of coronary heart disease and preparation method thereof.

Background technology

Coronary heart disease is the heart disease that causes myocardial ischemia, anoxia to cause owing to coronary atherosclerosis.Severe complications such as angina pectoris, myocardial infarction, ischemic cardiomyopathy, heart failure can appear in the patient, even die suddenly.In many developed countries, coronary heart disease is the modal cause of death, also is the reason that causes medical expense to increase fast.Although West Europe, the U.S., Australian Incidence of CHD at Central and Eastern Europe, also comprise Asia and Africa descending to a certain extent, evidence of coronary heart diseases is also in rapid rising.The domestic and international at present treatment to coronary heart disease mainly is a Western medicine, and as nitrate esters, calcium channel blocker such as nimodipine, beta-blocker, coronary artery dilator etc., these medicines all can produce side effect in various degree, and the patient is difficult to adhere to taking for a long time.For example: calcium channel blocker can make patient face flushing, headache, dizzy, cardiopalmus, gastrointestinal upset, drug withdrawal suddenly can increase the weight of myocardial ischemia.Beta-blocker can cause bradycardia, bronchospasm, weak, Raynaud phenomenon, and drug withdrawal suddenly also can cause angina pectoris.Except that said medicine, for a change blood samples of patients viscosity, prevention thrombosis often are aided with anticoagulant medicine such as aspirin, have taken bleeding tendency for a long time, also can bring out gastritis, gastric ulcer.Though the Chinese patent medicine of some treatment coronary heart disease is also arranged,, FUFANG DANSHEN PIAN peaceful etc. as Tongxinluo, arteria coronaria, effect is not fairly obvious.

Summary of the invention

The object of the present invention is to provide a kind of the have blood viscosity of improvement, the formation of atherosclerosis speckle, the Chinese medicine preparation of the treatment coronary heart disease of coronary blood flow increasing.

Another object of the present invention provides the preparation method of this Chinese medicine preparation.

Medicament of the present invention is made (consumption is a weight portion) by following raw material of Chinese medicine: Fructus Crataegi 5～35, Radix Puerariae 5～25, Rhizoma Dioscoreae 5～35, the Radix Paeoniae Alba 5～30, Rhizoma Smilacis Glabrae 5～35.Preferred weight (part) proportioning for preparing each raw material of medicament of the present invention is Fructus Crataegi 15～30, Radix Puerariae 10～20, Rhizoma Dioscoreae 15～30, the Radix Paeoniae Alba 15～25, Rhizoma Smilacis Glabrae 15～30.Optimum weight (part) proportioning is Fructus Crataegi 25, Radix Puerariae 15, Rhizoma Dioscoreae 25, the Radix Paeoniae Alba 20, Rhizoma Smilacis Glabrae 25.

Above-mentioned each component is made the capsular preparation method of medicament of the present invention carries out successively according to the following steps:

(1), Fructus Crataegi, Radix Puerariae, Rhizoma Dioscoreae, the Radix Paeoniae Alba, Rhizoma Smilacis Glabrae are cleaned, chopping decocts with water three times, 70～130 minutes for the first time, second and third time each 40～100 minutes, for the first time amount of water is 10 times of crude drug gross weight, second and third time amount of water is 7 times of crude drug gross weight;

(2), each time decoction liquor left standstill 16 hours, the leaching supernatant merges each time filtrate temperature is controlled at 50 ℃～60 ℃, it is 1.3～1.35 thick paste that heating is condensed into relative density;

(3), the thick paste with gained carries out drying, 4-10 hour drying time under 70 ℃ of-80 ℃ of temperature;

(4) dry postcooling is pulverized, sieving obtains powder then, at last powder is incapsulated.

The present invention preferably makes capsule, the primary raw material of system capsulae vacuus is a gelatin, in the production with A type gelatin and Type B gelatin mixed material feeding, and add suitable adjuvant, adjuvant can be selected from: glycerol, sodium carboxymethyl cellulose, HPMC, oleamide sodium sulfonate, agar, food colour, dodecyl sodium sulfate etc. can add correctives in case of necessity.Step (3) Chinese crude drug carries out drying under 70-80 ℃ of temperature after extraction is condensed into thick paste, available constant pressure and dry also can be used the vacuum decompression drying, 4-10 hour drying time, from drying baker, take out after cooling, be ground into the powder shape, and sieve with the 80-100 order, make and be yellowish-brown or auburn powder, can incapsulate.Making the capsule specification is the 0.5g/ grain, and usage is: oral, one time 3～4,3 times on the one, two weeks were a course of treatment.

Compose the row agent as in above-mentioned thick paste, adding an amount of water solublity,, just can make granule as dextrin, sucrose, granule 4g/ bag, usage is: take after mixing it with water, one time one bag, three times on the one, two weeks were a course of treatment.

Utilize routine techniques can also make various dosage forms such as tablet, pill in addition.

This preparation is principal agent with the Radix Puerariae, and its main effective ingredient is a puerarin, has the heart of improvement, brain microcirculation effect.Preparation of the present invention is also had a beta-receptor sample retardance, prevention epinephrine institute proarrhythmia, the effect that the atherosclerosis speckle forms.But coronary blood flow increasing reduces myocardial oxygen consumption and improves myocardium coefficient of oxygen utilization, the dilating coronary blood vessel bed, improves coronary circulation, increases the myocardial nutrition blood flow.The antagonism alloxan, glucose, the blood sugar increasing that epinephrine causes, the energy blood circulation promoting improves myocardial ischemia, obviously alleviate angina pectoris, improve the ischemic electrocardiogram, the speed of heartbeat is slowed down, myocardial contraction strengthens, aortic pressure (MAP) reduces, but the blood flow of ischemic region CC is reduced.Owing to have above pharmacological action, can reach the curative effect of treatment coronary heart disease.

1. pharmacodynamic study

The present invention can be by increasing the peripheral blood vessel perfusion flow of body, accordingly can coronary blood flow increasing, thus improve myocardial ischemia, alleviate angina pectoris and myocardial infarction.Test is divided into 4 groups at random with Rana nigromaculata, and every group 10 example is respectively normal saline group, nimodipine group, extracting solution high dose group of the present invention and low dose group.Relatively (variation of (ml/3min) the results are shown in Table 1 to administration front and back perfusate flow.

Table 1 extracting solution of the present invention is to the influence of Rana nigromaculata peripheral blood vessel perfusion flow (x ± s)

Group	Dosage (mg/kg)	N	Perfusate flow (ml/3min)
						Before the administration	After the administration	Value added
			Normal saline nimodipine extracting solution of the present invention extracting solution of the present invention	An amount of 20 50 100	10 10 10 10				2.8±0.5 2.7±0.4 2.5±0.4 2.6±0.4	2.7±0.5 3.3±0.4* 3.0±0.4 3.5±0.	-0.1 0.6 0.5 0.9

Annotate: self compares before and after the administration, * * P＜0.01.

As can be seen from the above table: extracting solution of the present invention can make body peripheral blood vessel perfusion flow increase, and increases with the increase of dosage, and its effect is almost suitable with the Western medicine nimodipine.

Extracting solution of the present invention can also make the metabolism of arterial endothelial cell hydroxyproline slow, and the collagen contents of inwall is reduced relatively, helps preventing platelet adhesion, assembles and thrombosis, so arteriosclerosis effect is preferably arranged.The blood plasma catechlolamine of hypertension and patients with coronary heart disease (GA) is than normal person height in addition, behind the quiet notes extracting solution of the present invention, and blood pressure drops, heart rate slows down, and blood plasma GA content obviously descends.(seeing Table 2)

Table 2 extracting solution of the present invention is to the influence of arterial endothelial cell (x ± s)

Group	Dosage (μ g/ml)	Interior liquid glycosaminoglycan (μ g/ml)	Outer liquid glycosaminoglycan (μ g/ml)	Interior liquid hydroxyproline (μ g/ml)	Outer liquid hydroxyproline (μ g/ml)
						Normal saline extracting solution of the present invention	An amount of 250	1.77±0.12 0.95±0.12	1.57±0.08 0.68±0.15	3.35±0.05 2.70±0.06	2.68±0.10 2.43±0.21

Annotate: compare * * P＜0.01 with the matched group normal saline.

Studies show that endotheliocyte covers the intravascular space surface, it is complete to keep the blood vessel structure endothelium, regulate the permeability of water solublity and blood plasma macromolecular substances, except that playing the selectivity barrier action, complicated enzyme system is also arranged, can synthesize and secrete many active substances such as PGI ₂Deng, if endotheliocyte in case damage fails to repair, then causes arteriosclerosis easily.Extracting solution of the present invention can make the interior liquid hydroxyproline metabolism of endotheliocyte slow, and the collagen contents of inwall is reduced relatively, helps preventing platelet adhesion, assembles and send out and thrombosis, so arteriosclerosis effect is preferably arranged.Be better than the conventional therapy of other Chinese patent medicines on the one hand greatly at this.

Medicament acute toxicity of the present invention and long term toxicity test: the LD of rat intravenous injection puerarin ₅₀Be 738mg/kg, the intravenous LD of this extracting solution ₅₀Can't measure, show that this preparation toxicity is extremely low, nontoxic substantially.Salmonella reversion test is negative, and chromosome aberration analysis does not show genetoxic, and micronucleus test does not demonstrate causing of target cell prominent active, and tertogenicity test does not have teratogenesis to the tire Mus.

2. clinical research is used:

Clinical trial 1

Whole cases are totally 60 examples, male 35 examples, women 25 examples.Be the acute cerebral infarction of the internal carotid artery system that takes place first.Be admitted to hospital in the 72h of morbidity back.Meet " all kinds of cerebrovascular disease diagnosis main points " standard that the 4th national cerebrovascular meeting passed through.Be divided into treatment group and matched group at random by the order of being admitted to hospital, each 30 example.When two groups of patients are admitted to hospital the age be respectively (62 ± 8) year and (62 ± 9) year; Neurologic impairment is respectively (26 ± 9) and (25 ± 9) and divides.Morbidity is respectively (28 ± 15) h and (28 ± 16) h, there was no significant difference to beginning administration time.Add quiet of 5%GS 500ML with extracting solution 500mg of the present invention, 1 time/d, 14d is 1 course of treatment, uses 2 courses of treatment continuously.Do not accept the medicine of other treatment coronary heart disease during the medication.Matched group: with quiet of low right 500ML, 1 time/d, the course of treatment is with the treatment group.Before medication, reach 2 end back extractions courses of treatment venous bloods mensuration hemorheology index on an empty stomach, add up the variation of 2 groups of patient treatments front and back whole blood viscosity respectively.The high shear rate of treatment group treatment back hemorheology, middle shear rate, low shear rate.The results are shown in Table 3:

Table 3 extracting solution of the present invention is to the influence of acute cerebral infarction patient's whole blood viscosity (x ± s)

Group		HCT	Whole blood viscosity
						Height is cut (200s -1)	In cut (30s -1)	Low (the 3s that cuts -1)
			The treatment group	After treating before the treatment	0.46±0.04 0.45±0.04				6.7±0.5 6.2±0.6*	8.8±0.4 7.8±0.7	12.9±1.1 12.0±1.1*
Matched group	After treating before the treatment	0.45±0.05 0.41±0.05*				6.5±0.5 6.6±0.6	9.7±0.6 9.5±0.5	12.9±1.1 12.1±1.7

Annotate: the t check, compare P＜0.05 before * and the treatment of this group

The present invention has stronger antioxidant radical effect, can be by removing oxygen-derived free radicals and anti peroxidation of lipid, make the ANOMALOUS VARIATIONS of blood viscosity return to normal condition, simultaneously can reduce acute cerebral infarction patient's whole blood viscosity, platelet aggregation and external thrombus are formed with the obvious suppression effect, highly beneficial for control angina pectoris and myocardial infarction.

Clinical trial 2

Ischemic heart desease diagnostic criteria according to International Society of Cardiology in 1979 and association and World Health Organization (WHO) (ISFC/WHO) name, select to be diagnosed as the same period angina pectoris patient 58 examples in hospital, be angina pectoris and show effect repeatedly, resting electrocardiogram has ischemic ST-T to change.Be divided into 2 groups at random, capsule treatment group of the present invention (treatment group) 35 examples, male 21 examples, women 14 examples; Age is respectively (62 ± 9) years (38～76 years old); Fatigue angina pectoris 19 examples wherein, spontaneous angina pectoris 16 examples, complicated hypertension 30 examples; The course of disease is respectively (6 ± 4) year, (1 month～31 years).FUFANG DANSHEN PIAN group (matched group) 23 examples, male 14 examples, women 9 examples; Age is respectively ((60 ± 7) year, (40～71 years old); Fatigue angina pectoris 12 examples wherein, spontaneous angina pectoris 11 examples, complicated hypertension 19 examples; The course of disease is respectively (7 ± 5) year, (3 months～18 years).

Therapeutic Method: matched group adopts 3 of FUFANG DANSHEN PIAN oral a time, 3 days on the one, 14 days courses of treatment; The treatment group is taken capsule of the present invention, and is oral, one time 3～4,3 times on the one, 14 days courses of treatment.

Observation index: observe two groups of patient's medications every day front and back hearts rate, blood pressure, myocardial oxygen consumption, angina pectoris attacks situation.Do resting electrocardiogram, hepatic and renal function, blood glucose, blood fat, hematuria routine examination around the course of treatment.

Curative effect judging standard

Produce effects: the angina pectoris attacks number of times reduces more than 80%, and it is normal that resting electrocardiogram recovers.

Effectively: the angina pectoris attacks number of times reduces 50%～80%, and electrocardiogram improves, and the above or negative T wave that mainly leads of ST section rise 0.5mm shoals and reaches more than 50%.

Invalid: angina pectoris attacks reduces＜50%, the resting electrocardiogram no change.Curative effect relatively sees Table 4,5

Table 4 capsule of the present invention and FUFANG DANSHEN PIAN treatment angina pectoris curative effect are relatively

Project	Group	Produce effects	Effectively	Invalid	Total effectively (%)
						The doing well,improving situation	The treatment group	9	22	4	88.57*
Matched group	3	11	9	60.87
					Electrocardiogram improves situation		The treatment group	7	22	6	82.86**
Matched group	2	9	12	47.83

Annotate: compare * P＜0.05, * * P＜0.01 with controlling matched group

As seen from the above table, capsule of the present invention is relief of symptoms effectively, reduces anginal attack times, improves electrocardiogram, and its curative effect is better than FUFANG DANSHEN PIAN.

Compare before and after table 6 liang group average systolic, heart rate, the myocardial oxygen consumption treatment

Group	Average systolic (mmhg)		Average heart rate (inferior/min)		Myocardial oxygen consumption (kPa/min)
							Before the treatment	After the treatment	Before the treatment	After the treatment	Before the treatment	After the treatment
	The treatment group	168.83	152.25*	79.45	70.83*	13413.15							10783.87 *
Matched group							166.50	158.25	78.32	77.23	13040.25	12221.62 *

Annotate: with compare * P＜0.05, * * P＜0.01 before the treatment

As seen from the above table, capsule energy decreased heart rate of the present invention reduces myocardial oxygen consumption, and its curative effect is better than FUFANG DANSHEN PIAN.

Period in a medicine is not seen untoward reaction.

Conclusion: observe by above pharmacodynamic study, clinical verification and untoward reaction, point out Chinese medicine preparation energy coronary blood flow increasing of the present invention, improve heart, brain microcirculation, the atherosclerosis speckle forms simultaneously, toxic and side effects is minimum, for control angina pectoris and myocardial infarction good effect is arranged.

The specific embodiment: (totally 6 examples)

Embodiment 1

Take by weighing raw material (kilogram) by following weight proportion: Fructus Crataegi 25, Radix Puerariae 15, Rhizoma Dioscoreae 25, the Radix Paeoniae Alba 20, Rhizoma Smilacis Glabrae 25.Production method is as follows:

Raw material is cleaned, and chopping decocts with water three times, and 100 minutes for the first time, second and third time each 70 minutes.Add for the first time i.e. 1100 kilograms the water of 10 times of amounts, second and third time respectively adds i.e. 770 kilograms the water of 7 times of amounts, and each time decoction liquor left standstill 16 hours, the leaching supernatant merges each time filtrate, and temperature is controlled at 50 ℃, be condensed into relative density and be 1.3 thick paste, be condensed into thick paste after, constant pressure and dry under 70 ℃ of temperature, 5 hours drying times, from drying baker, take out after cooling, be ground into the powder shape, and sieve with 80 orders, make and be yellowish-brown or auburn powder, can incapsulate.Making the capsule specification is the 0.5g/ grain, reinstalls in the bottle after aluminum-plastic packaged to seal.

Embodiment 2

Take by weighing raw material (kilogram) by following weight proportion: Fructus Crataegi 5, Radix Puerariae 15, Rhizoma Dioscoreae 5, the Radix Paeoniae Alba 5, Rhizoma Smilacis Glabrae 35.Production method is as follows:

Raw material is cleaned, and chopping decocts with water three times, and 70 minutes for the first time, second and third time each 40 minutes.Add for the first time i.e. 650 kilograms the water of 10 times of amounts, second and third time respectively adds i.e. 455 kilograms the water of 7 times of amounts, and each time decoction liquor left standstill 16 hours, the leaching supernatant merges each time filtrate, and temperature is controlled at 55 ℃, be condensed into relative density and be 1.35 thick paste, be condensed into behind the thick paste vacuum decompression drying under 80 ℃ of temperature, 4 hours drying times, from drying baker, take out after cooling, be ground into the powder shape, and sieve with 100 orders, make and be yellowish-brown or auburn powder, can incapsulate.Making the capsule specification is the 0.5g/ grain, reinstalls in the bottle after aluminum-plastic packaged to seal.

Embodiment 3

Take by weighing raw material (kilogram) by following weight proportion: Fructus Crataegi 35, Radix Puerariae 5, Rhizoma Dioscoreae 20, the Radix Paeoniae Alba 10, Rhizoma Smilacis Glabrae 15.Production method is as follows:

Raw material is cleaned, and chopping decocts with water three times, and 130 minutes for the first time, second and third time each 100 minutes.Add for the first time i.e. 850 kilograms the water of 10 times of amounts, second and third time respectively adds i.e. 595 kilograms the water of 7 times of amounts, and each time decoction liquor left standstill 16 hours, the leaching supernatant merges each time filtrate, and temperature is controlled at 60 ℃, be condensed into relative density and be 1.3 thick paste, be condensed into behind the thick paste vacuum decompression drying under 80 ℃ of temperature, 10 hours drying times, from drying baker, take out after cooling, be ground into the powder shape, and sieve with 90 orders, make and be yellowish-brown or auburn powder, can incapsulate.Making the capsule specification is the 0.5g/ grain, reinstalls in the bottle after aluminum-plastic packaged to seal.

Embodiment 4

Take by weighing raw material (kilogram) by following weight proportion: Fructus Crataegi 15, Radix Puerariae 25, Rhizoma Dioscoreae 35, the Radix Paeoniae Alba 30, Rhizoma Smilacis Glabrae 5.Production method is as follows:

Raw material is cleaned, and chopping decocts with water three times, and 90 minutes for the first time, second and third time each 50 minutes.Add for the first time i.e. 1100 kilograms the water of 10 times of amounts, second and third time respectively adds i.e. 770 kilograms the water of 7 times of amounts, and each time decoction liquor left standstill 16 hours, the leaching supernatant merges each time filtrate, and temperature is controlled at 50 ℃, be condensed into relative density and be 1.3 thick paste, be condensed into behind the thick paste constant pressure and dry under 80 ℃ of temperature, 8 hours drying times, from drying baker, take out after cooling, be ground into the powder shape, and sieve with 90 orders, make and be yellowish-brown or auburn powder, can incapsulate.Making the capsule specification is the 0.5g/ grain, reinstalls in the bottle after aluminum-plastic packaged to seal.

Embodiment 5

Take by weighing raw material (kilogram) by following weight proportion: Fructus Crataegi 25, Radix Puerariae 20, Rhizoma Dioscoreae 30, the Radix Paeoniae Alba 20, Rhizoma Smilacis Glabrae 25.Production method is as follows:

Raw material is cleaned, and chopping decocts with water three times, and 110 minutes for the first time, second and third time each 60 minutes.Add for the first time i.e. 1200 kilograms the water of 10 times of amounts, second and third time respectively adds i.e. 840 kilograms the water of 7 times of amounts, and each time decoction liquor left standstill 16 hours, the leaching supernatant merges each time filtrate, and temperature is controlled at 50 ℃, be condensed into relative density and be 1.3 thick paste, be condensed into behind the thick paste vacuum decompression drying under 80 ℃ of temperature, 9 hours drying times, from drying baker, take out after cooling, be ground into the powder shape, and sieve with 100 orders, make and be yellowish-brown or auburn powder, can incapsulate.Making the capsule specification is the 0.5g/ grain, reinstalls in the bottle after aluminum-plastic packaged to seal.

Embodiment 6

Take by weighing raw material (kilogram) by following weight proportion: Fructus Crataegi 25, Radix Puerariae 15, Rhizoma Dioscoreae 25, the Radix Paeoniae Alba 20, Rhizoma Smilacis Glabrae 25.Production method is as follows:

Raw material is cleaned, and chopping decocts with water three times, and 120 minutes for the first time, second and third time each 80 minutes.Add for the first time i.e. 1100 kilograms the water of 10 times of amounts, second and third time respectively adds i.e. 770 kilograms the water of 7 times of amounts, each time decoction liquor left standstill 16 hours, and the leaching supernatant merges each time filtrate, temperature is controlled at 53 ℃, be condensed into relative density and be 1.32 thick paste, above-mentioned thick paste is baked the dried powder that soaks, soak the water solublity that powder adds appropriate amount and compose row agent dextrin dried then, stirring and evenly mixing makes granule.Specification is the 4g/ bag, aluminum-plastic packaged sealing.

Claims (6)

1. Chinese medicine preparation for the treatment of coronary heart disease is characterized in that wherein making that raw materials of effective components is formed and weight proportion is: Fructus Crataegi 5～35, Radix Puerariae 5～25, Rhizoma Dioscoreae 5～35, the Radix Paeoniae Alba 5～30, Rhizoma Smilacis Glabrae 5～35.

2. the Chinese medicine preparation of treatment coronary heart disease as claimed in claim 1, wherein the weight proportion of each raw material is: Fructus Crataegi 15～30, Radix Puerariae 10～20, Rhizoma Dioscoreae 15～30, the Radix Paeoniae Alba 15～25, Rhizoma Smilacis Glabrae 15～30.

3. the Chinese medicine preparation of treatment coronary heart disease as claimed in claim 1, wherein the weight proportion of each raw material is Fructus Crataegi 25, Radix Puerariae 15, Rhizoma Dioscoreae 25, the Radix Paeoniae Alba 20, Rhizoma Smilacis Glabrae 25.

4. as the Chinese medicine preparation of claim 1,2 or 3 described treatment coronary heart disease, wherein said medicament is a said dosage form on any pharmaceutics.

5. the Chinese medicine preparation of treatment coronary heart disease as claimed in claim 4, wherein said dosage form is a capsule.

6. the Chinese medicine preparation of treatment coronary heart disease as claimed in claim 5, its preparation method carry out successively according to the following steps:

(1), Fructus Crataegi, Radix Puerariae, Rhizoma Dioscoreae, the Radix Paeoniae Alba, Rhizoma Smilacis Glabrae are cleaned, chopping decocts with water three times, 70～130 minutes for the first time, second and third time each 40～100 minutes, for the first time amount of water is 10 times of crude drug gross weight, second and third time amount of water is 7 times of crude drug gross weight;

(2), each time decoction liquor left standstill 16 hours, the leaching supernatant merges each time filtrate temperature is controlled at 50 ℃～60 ℃, it is 1.3～1.35 thick paste that heating is condensed into relative density;

(3), the thick paste with gained carries out drying, 4-10 hour drying time under 70 ℃ of-80 ℃ of temperature;

(4) dry postcooling is pulverized, sieving obtains powder then, at last powder is incapsulated.