CN107468752A - A kind of compound Danshen Root sticks micropill and its preparation technology - Google Patents

Abstract

The invention discloses a compound Danshen adhered pellet and a preparation method thereof, which is mainly characterized in that Danshen, Panax notoginseng, borneol and Danshen notoginseng are respectively extracted with 70% ethanol to obtain the extract, and the borneol is wrapped with beta-cyclodextrin Take its clathrate, and use the extrusion spheronizer to prepare pellets. The compound salvia miltiorrhiza adhered pellets prepared by the present invention can make the drug adhere to the gastrointestinal mucosa of the human body, prolong the residence time of the drug in the gastrointestinal tract, and can significantly Improve the bioavailability of the compound Danshen formula, and at the same time, the inclusion of borneol with beta-cyclodextrin can improve the stability of borneol in the preparation.

Description

A kind of compound salvia miltiorrhiza adhered pellets and its preparation process

technical field

The invention relates to the field of traditional Chinese medicines, in particular to compound salvia miltiorrhiza sticky pellets and a preparation process thereof.

Background technique

Compound salvia miltiorrhiza preparation is one of the large varieties of well-known Chinese patent medicines. It is widely used clinically to treat coronary heart disease, angina pectoris and other cardiovascular diseases with definite curative effect. Compound Salvia Recipe consists of three traditional Chinese medicines, Danshen, Panax notoginseng and Borneol. The fat-soluble components of Danshen, represented by tanshinone ⅡA, diterpene quinones are poorly dissolved, and the water-soluble components represented by salvianolic acid B and saponins in Panax notoginseng have poor stability in gastric juice. Refreshing, heat-clearing and toxin-dispelling effects, but borneol is volatile, and long-term storage may lead to a decrease in the content of medicinal ingredients in the preparation.

Bioadhesion technology can solve the problem of insufficient residence time of drugs in the gastrointestinal tract. It increases the force between the drug and the gastrointestinal mucosa, prolongs the residence time of the drug in the gastrointestinal tract, and promotes the close contact between the drug and the mucosa. Improve the bioavailability of drugs. The inclusion technology of beta-cyclodextrin can effectively prevent the volatilization of borneol during production and storage.

Contents of the invention

The object of the present invention is to provide a kind of compound Danshen adherent pellet, and the object of the present invention is realized through the following technical scheme:

A compound salvia miltiorrhiza adherent pellet, which weighs 6-10 parts by weight of Danshen extract, 1-3 parts by weight of Panax notoginseng extract, 1-4 parts by weight of borneol inclusion compound, and 1-3 parts by weight of hydroxypropyl methylcellulose _K100M parts by weight, 1-3 parts by weight of chitosan, 1-3 parts by weight of carbomer 934P, 2-7 parts by weight of microcrystalline cellulose, mix well, add 10-15 parts by volume of 20-40% aqueous sodium chloride solution, The pellets were prepared by extrusion and spheronization, and the compound salvia miltiorrhiza adhering pellets were obtained;

The compound Danshen adherent pellets of the present invention are preferably prepared by the following method:

Weigh 8.09 parts by weight of Salvia miltiorrhiza extract, 1.57 parts by weight of Panax notoginseng extract, 2.176 parts by weight of borneol inclusion compound, 2.5 parts by weight each of hydroxypropyl methylcellulose _K100M , chitosan, and carbomer 934P, microcrystalline fiber 5.56 parts by weight of Su, mixed evenly, adding 20-40% sodium chloride aqueous solution, adopting extrusion spheronization method to prepare compound salvia miltiorrhiza adhering pellets, and drying to obtain.

Described salvia miltiorrhiza extract, Panax notoginseng extract are made by conventional method;

Described borneol clathrate is made by following method:

Weigh 4-8 parts by weight of beta-cyclodextrin, place it in a ball milling jar, add 10-30 parts by volume of distilled water; weigh 0.5-2 parts by weight of borneol, add absolute ethanol to dissolve, add the solution into a ball milling jar, Grind, take out, place overnight at 3-5°C, filter, wash the adsorbed borneol on the filter cake with absolute ethanol, dry at 40-60°C under reduced pressure, grind finely and pass through an 80-mesh sieve to obtain borneol beta cyclopaste Fine clathrate.

The salvia miltiorrhiza extract or Panax notoginseng extract is preferably prepared as follows:

Danshen decoction pieces or Panax notoginseng decoction pieces, add 6-10 times by weight 60-90% ethanol to reflux extract 1-3 times, each time 1-2h, filter, combine extracts, concentrate to thick paste, dry under reduced pressure at 40-70°C , to obtain Danshen extract or Panax notoginseng extract.

The relationship between parts by weight and parts by volume in the present invention is the relationship of g/ml.

Description of drawings:

Fig. ₁ R1 plasma concentration-time curve in the compound salvia miltiorrhiza preparation

Fig. 2 _Rg1 plasma concentration-time curve in compound Danshen preparation

_Re blood drug concentration-time curve in Fig. 3 compound salvia miltiorrhiza preparation

R _b1 plasma concentration-time curve in Fig. 4 compound salvia miltiorrhiza preparation

R _d plasma concentration-time curve in Fig. 5 compound salvia miltiorrhiza preparation

The present invention uses hydroxypropyl methylcellulose _K100M , chitosan and carbomer 934P as adhesive materials, and adopts the method of extruding and spheronizing pellets to prepare compound Danshen prescription into compound Danshen adherent pellets, thereby increasing the content of compound Danshen prescription. The residence time of each drug in the body prolongs the release of the drug in the body and improves the bioavailability of the drug. The borneol of the present invention is clathrated with beta-cyclodextrin, and the clathrate technology can effectively prevent volatilization of the borneol during production and storage, and enhance the stability of the borneol in the preparation.

Experimental Example 1: Adhesion Performance Test of Compound Danshen Adhesive Pellets in Example 1

1 In vitro adhesion test

1.1 Tissue residue method

Fresh porcine small intestines were taken, and the contents of the small intestines were washed away with pH6.8 phosphate buffer solution, cut into 10cm intestines, cut lengthwise, spread on a glass plate, and fixed with long tail clips. Take 100 pellets, sprinkle them evenly on the surface of the intestinal mucosa, oscillate in the artificial intestinal fluid at 37°C, the oscillation frequency is 100 times/min, and count the number of pellets remaining on the surface of the intestinal mucosa after a certain period of time. The experimental results are shown in Table 1.

Table 1 Results of adhesion test by tissue residue method (n=2)

1.2 Minimum peel force method

Take fresh porcine small intestine, wash away the contents in the small intestine with pH6.8 phosphate buffer solution, cut into 10cm intestine section, cut it longitudinally, and stick it on the small intestine with four 2cm wide adhesive tapes, two at each end, each other Do not overlap, leave a 2cm wide gap in the middle, weigh 0.5g of adhesive pellets, sprinkle evenly on the small intestine, take 0.5mL of pH6.8 phosphate buffer, drop on the pellets, make the pellets fully swell, Take another fresh pig small intestine, cut it longitudinally so that the inner surface sticks to the small intestine, cover it with a glass plate of the same size, press it with a pressure of 6N for 20 minutes, put it on the peeling tester, clamp a section, and start, Record the value that the small intestine moves at the beginning, that is, the maximum value, which is the minimum peeling force. The experimental results are shown in Table 2.

Table 2 Minimum peel force test results (n=2)

2 In vivo adhesion test

SD rats were fasted for 24 hours and had free access to water. Each rat was given 100 pellets of different prescriptions and fed with 1 mL of normal saline. After administration, the rats were fasted from food and water. After 4 hours, the rats were sacrificed, dissected, the stomach and small intestine were taken out, and spread horizontally on a white enamel plate. The remaining length of each segment of the small intestine. The adhesion length of the pellets in each section of the small intestine is weighted, the upper section (L ₁ ) is more weighted, the middle section (L ₂ ) is next, and the lower section (L ₃ ) is the least weighted. Adhesion index N=0.5L ₁ +0.3L ₂ +0.2L ₃ , see Table 3 for the experimental results.

Table 3 In vivo adhesion test results (n=2)

The results of in vivo and in vitro adhesion tests show that the compound Danshen adherent pellets of the present invention have good adhesion properties.

Experimental Example 2: Comparative study on blood concentration of index components R ₁ , Rb ₁ , Re, Rd ₁ , Rg ₁ in Compound Danshen Adhesive Pellets and Common Compound Danshen Pellets in Example 2

Twelve male SD rats weighing 240-260 g were fed adaptively for 1 week, and were randomly divided into two groups: Group 1 was the compound Danshen Zhuanzhuan pellet group; group 2 was the ordinary compound Danshen pellet group. Administer at 2.4g/kg, take 0.5mL of blood from the orbit at the specified time point, put it in a heparin tube, and centrifuge at 5000r/min for 15min, take 200μL of the supernatant, and add 10μL (500ng/mL) of saikosaponin A and 600 μL of acetonitrile, vortexed for 3 minutes, centrifuged at 14000 r/min for 10 minutes, and the supernatant was evaporated to dryness in a vacuum concentrator at 40°C. Add 100μL of 20% acetonitrile solution to redissolve, vortex for 2min, place in an ultrasonic instrument for 10min at 100w power, centrifuge at 14000r/min for 10min, repeat centrifugation three times, and take the supernatant as the test solution.

The average blood drug concentration-time curves of index components R1, Rg1, Re, Rb1, Rd in Compound Danshen Adhesive Pellets and Compound Danshen Ordinary Preparation are shown in Figure 1-Figure 5, and the corresponding pharmacokinetic fitting parameters are shown in Table 4-Table 8

Table 4 R ₁ pharmacokinetic fitting parameters (n=6, mean±SD)

Note: * indicates that there is a significant difference between compound Danshen sticky pellets and compound Danshen common preparation, P<0.05.

Table 5 Pharmacokinetic fitting parameters of Rg ₁ (n=6, mean±SD)

Note: * indicates that there is a significant difference between compound Danshen sticky pellets and compound Danshen common preparation, P<0.05.

Table 6 Re pharmacokinetic fitting parameters (n=6, mean±SD)

Note: * indicates that there is a significant difference between compound Danshen sticky pellets and compound Danshen common preparation, P<0.05.

Table 7 Pharmacokinetic fitting parameters of Rb ₁ (n=6, mean±SD)

Note: * indicates that there is a significant difference between compound Danshen sticky pellets and compound Danshen common preparation, P<0.05.

Table 8 Pharmacokinetic fitting parameters of Rd (n=6, mean±SD)

Note: * indicates that there is a significant difference between compound Danshen sticky pellets and compound Danshen common preparation, P<0.05.

From the above results, it can be seen that the bioavailability of the five saponin components in the compound Danshen Adhesive Pellets is greater than that of the common preparation. For the five ingredients as a whole, the CLz/F of the adhesive preparation was significantly lower than that of the common preparation, and the AUC and _Cmax of the adhesive preparation were significantly higher than that of the common preparation, indicating that the adhesive preparation played an adhesive effect in vivo, and adhesion on the mucous membrane indicated The drug is in closer contact with it, and the absorption efficiency is higher. At the same time, the effective absorption time of the drug is prolonged, and a greater blood concentration is provided to the body, so that the bioavailability is significantly improved and better curative effect is provided.

Example 1:

Add 450g of Danshen decoction pieces and add 8 times the amount of 70% ethanol to reflux and extract twice, each time for 1.5h, filter, combine the extracts, concentrate to a thick paste, and dry under reduced pressure at 60°C to obtain the Danshen extract with a paste yield of 42.8%. Grind the salvia miltiorrhiza extract, pass through a 80-mesh sieve, and set aside; Add 8 times the amount of 70% ethanol to 141g of Panax notoginseng decoction pieces, reflux and extract twice, each time for 1.5h, filter, combine the extracts, concentrate to a thick paste, and depressurize at 60°C Dry to obtain the extract of Panax notoginseng, the yield of the paste is 26.43%. The extract of Panax notoginseng is ground, passed through an 80-mesh sieve, and set aside; weigh 6g of beta-cyclodextrin, put it in a ball mill jar, add 20mL of distilled water; weigh Add 1g of borneol (passed through 80 mesh sieve), add 2mL of absolute ethanol to dissolve, put the solution into a ball mill jar at a speed of 300r·min ^-1 , grind for 30min, take it out, put it in a refrigerator at 4°C overnight, filter, and use 5mL of Wash the adsorbed borneol on the filter cake with water and ethanol, and dry under reduced pressure at 50°C for 6 hours to obtain the borneol-beta-cyclodextrin inclusion compound, which is ground and passed through an 80-mesh sieve for later use. The yield of the paste is 680%.

Take by weighing 8.09g of Salvia miltiorrhiza extract (the yield of salvia miltiorrhiza is 42.5%), 1.57g of Radix Notoginseng extract (26.43% of the yield of Panax notoginseng), 2.176g of borneol inclusion compound (the yield of cream of Radix Notoginseng is 680%), hydroxypropyl 2.5 g each of methylcellulose _K100M , chitosan, and carbomer 934P, 5.56 g of microcrystalline cellulose, mixed evenly, added 12 mL of 30% sodium chloride aqueous solution, and prepared compound Danshen adherent pellets by extrusion spheronization. The extrusion speed is 25r/min, the spheronization speed is 1600r/min, the spheronization time is 4min, and the drying time is 2h.

Example 2: 450 g of Danshen decoction pieces were added with 8 times the amount of 70% ethanol for reflux extraction twice, each time for 1.5 hours, filtered, combined extracts, concentrated, and dried under reduced pressure at 60°C to obtain Danshen extract with a paste yield of 44.92% , the extract of Salvia miltiorrhiza was finely ground, passed through a 80-mesh sieve, and set aside; 141g of Sanqi decoction pieces were added with 8 times the amount of 70% ethanol for reflux extraction twice, each time for 1.5h, filtered, combined extracts, concentrated, and dried under reduced pressure at 60°C. The extract of Panax notoginseng was obtained, and the paste yield was 29.88%. The extract of Panax notoginseng was finely ground, passed through an 80-mesh sieve, and set aside; weighed 6g of beta-cyclodextrin, put it in a ball mill jar, added 20mL of distilled water; weighed 1g of borneol (through a 80-mesh sieve), add 2 mL of absolute ethanol to dissolve, put the solution into a ball mill jar, grind for 30 min at 300 r·min ^-1 , take it out, place it in a refrigerator at 4°C overnight, filter, and wash with 5 mL of absolute ethanol The borneol adsorbed on the filter cake was dried under reduced pressure at 50°C for 6 hours, ground and passed through an 80-mesh sieve to obtain the borneol-beta-cyclodextrin inclusion compound, which was ready for use, and the paste yield was 680%.

Salvia miltiorrhiza extract 8.02g (cream yield 44.92%), Panax notoginseng extract 1.67g (cream yield 29.88%), borneol inclusion compound 2.176g, hydroxypropyl methylcellulose _K100M , chitosan, carbomer 934P, 2.5g each, 5.634g microcrystalline cellulose, mix well, add 12mL of 30% sodium chloride aqueous solution, extrusion speed is 25r/min, spheronization speed is 1600r/min, spheronization time is 4min, drying time is 2h, Instantly.

Claims (8)

1. a kind of compound Danshen Root sticks micropill, it is characterised in that the micropill is made by the following method：

Weigh Salvia root P.E 6-10 parts by weight, Notogineng Extract 1-3 parts by weight, borneol inclusion compound 1-4 parts by weight, hydroxypropyl first Base cellulose_K100M1-3 parts by weight, chitosan 1-3 parts by weight, carbomer940 1-3 parts by weight, microcrystalline cellulose 2-7 weight Part, mix, add 20-40% sodium-chloride water solution 10-15 parts by volume, micropill is prepared using extrusion spheronization method, produce compound pellet Ginseng sticks micropill；

The Salvia root P.E, Notogineng Extract have conventional method to be made；

The borneol inclusion compound is made by the following method：

Betadex 4-8 parts by weight are weighed, are placed in ball grinder, add 10-30 parts by volume distilled water；Weigh borneol 0.5-2 Parts by weight, add absolute ethyl alcohol to dissolve, the solution is added in ball grinder, grind, take out, stood overnight with 3-5 DEG C, filter, use The borneol that adsorbs on absolute ethyl alcohol washing filter cake, puts 40-60 DEG C and is dried under reduced pressure, the finely ground mesh sieve of mistake 80, produces borneol times his ring paste Inclusion compounds.

2. compound Danshen Root as claimed in claim 1 sticks micropill, it is characterised in that the micropill is made by the following method：

Weigh the parts by weight of Salvia root P.E 8.09, the parts by weight of Notogineng Extract 1.57, the parts by weight of borneol inclusion compound 2.176, hydroxypropyl Ylmethyl cellulose_K100M, chitosan, each 2.5 parts by weight of carbomer940, the parts by weight of microcrystalline cellulose 5.56, mix, add The parts by volume of 30% sodium-chloride water solution 12, compound Danshen Root is prepared using extrusion spheronization method and sticks micropill.

3. compound Danshen Root as claimed in claim 1 or 2 sticks micropill, it is characterised in that the Salvia root P.E or pseudo-ginseng extraction Thing is prepared by the following method：

Salvia piece or notoginseng decoction piece, add 6-10 times of weight 60-90% alcohol refluxs to extract 1-3 times, each 1-2h, filter, close And extract solution, thick paste is concentrated into, 40-70 DEG C is dried under reduced pressure, and obtains Salvia root P.E or Notogineng Extract.

4. compound Danshen Root as claimed in claim 1 or 2 sticks micropill, it is characterised in that the borneol inclusion compound is by the following method Prepare：

The parts by weight of betadex 6 are weighed, are placed in ball grinder, add 20 parts by volume distilled water；The parts by weight of borneol 1 are weighed, add 2 Parts by volume absolute ethyl alcohol dissolves, and the solution is added in ball grinder, 300rmin^-1, 30min is ground, is taken out, and in 4 DEG C of refrigerators Stand overnight, filter, the borneol adsorbed on filter cake is washed with 5 parts by volume absolute ethyl alcohols, 50 DEG C is put and is dried under reduced pressure 6h, finely ground mistake 80 Mesh sieve, produce borneol betadex inclusion compound.

5. a kind of compound Danshen Root sticks the preparation method of micropill, it is characterised in that this method is：

Weigh Salvia root P.E 6-10 parts by weight, Notogineng Extract 1-3 parts by weight, borneol inclusion compound 1-4 parts by weight, hydroxypropyl first Base cellulose_K100M1-3 parts by weight, chitosan 1-3 parts by weight, carbomer940 1-3 parts by weight, microcrystalline cellulose 2-7 weight Part, mix, add 20-40% sodium-chloride water solution 10-15 parts by volume, micropill is prepared using extrusion spheronization method, produce compound pellet Ginseng sticks micropill；

The Salvia root P.E, Notogineng Extract have conventional method to be made；

The borneol inclusion compound is made by the following method：

Betadex 4-8 parts by weight are weighed, are placed in ball grinder, add 10-30 parts by volume distilled water；Weigh borneol 0.5-2 Parts by weight, add absolute ethyl alcohol to dissolve, the solution is added in ball grinder, grind, take out, stood overnight with 3-5 DEG C, filter, use The borneol that adsorbs on absolute ethyl alcohol washing filter cake, puts 40-60 DEG C and is dried under reduced pressure, the finely ground mesh sieve of mistake 80, produces borneol times his ring paste Inclusion compounds.

6. compound Danshen Root as claimed in claim 1 sticks the preparation method of micropill, it is characterised in that this method is：

Weigh the parts by weight of Salvia root P.E 8.09, the parts by weight of Notogineng Extract 1.57, the parts by weight of borneol inclusion compound 2.176, hydroxypropyl Ylmethyl cellulose_K100M, chitosan, each 2.5 parts by weight of carbomer940, the parts by weight of microcrystalline cellulose 5.56, mix, add The parts by volume of 30% sodium-chloride water solution 12, compound Danshen Root is prepared using extrusion spheronization method and sticks micropill.

7. compound Danshen Root as claimed in claim 1 or 2 sticks the preparation method of micropill, it is characterised in that red described in this method Conopsea extraction or Notogineng Extract are prepared by the following method：

Salvia piece or notoginseng decoction piece, add 6-10 times of weight 60-90% alcohol refluxs to extract 1-3 times, each 1-2h, filter, close And extract solution, thick paste is concentrated into, 40-70 DEG C is dried under reduced pressure, and obtains Salvia root P.E or Notogineng Extract.

8. compound Danshen Root as claimed in claim 1 or 2 sticks the preparation method of micropill, it is characterised in that ice described in this method Piece inclusion compound is prepared by the following method：

The parts by weight of betadex 6 are weighed, are placed in ball grinder, 20 parts by volume distilled water is added, weighs the parts by weight of borneol 1, add 2 Parts by volume absolute ethyl alcohol dissolves, and the solution is added in ball grinder, 300rmin^-1, 30min is ground, is taken out, and in 4 DEG C of refrigerators Stand overnight, filter, the borneol adsorbed on filter cake is washed with 5 parts by volume absolute ethyl alcohols, 50 DEG C is put and is dried under reduced pressure 6h, finely ground mistake 80 Mesh sieve, produce borneol betadex inclusion compound.