Traditional Chinese medicine composition and preparation method and application thereof

Abstract

A traditional Chinese medicine composition, made from cassia twig, poria, Cortex moutan, Radix paeoniae alba, peach kernel in equal proportions. The traditional Chinese medicine composition comprises paeoniflorin, amygdalin, benzoylpaeoniflorin, cinnamic acid, paeonol, and cinnamaldehyde. The composition has the advantages of high production efficiency, high content of effective ingredients, high transfer rate of poria acid, reduced hygroscopicity, and improved dissolution of index ingredients.

Claims

1. A method for preparing a traditional Chinese medicine composition comprising Ramulus cinnamomi, Poria cocos, Cortex moutan, Radix paeoniae alba, and peach kernel in equal proportions, comprising following steps: (a) preparation of a Poria cocos powder intermediate: pulverizing 30-49% of the Poria cocos to obtain the Poria cocos powder intermediate; (b) preparation of a paeonol inclusion compound: extracting paeonol from Cortex moutan by direct connection steam distillation, and collecting aromatic water and medicinal dregs for use later; resting the aromatic water for 48-72 hours until crystals are completely crystallized, and filtering and drying in shade to obtain paeonol crystals; and including with β-cyclodextrin to prepare a paeonol inclusion compound; (c) preparation of a Ramulus cinnamomi volatile oil inclusion compound: extracting volatile oil from Ramulus cinnamomi by direct connection steam distillation, adding ethyl acetate during the extracting process, and collecting aromatic water from ethyl acetate layers and medicinal dregs for use later; placing the aromatic water in a separating funnel, resting the aromatic water, separating an upper ethyl acetate layer, extracting a lower layer with equal amount of ethyl acetate, combining the ethyl acetate layers, carrying out reduced-pressure recovery, and adding ethanol for further concentration to obtain pure volatile oil; including with β-cyclodextrin to prepare the Ramulus cinnamomi volatile oil inclusion compound; (d) preparation of spray-dried powder intermediates of extracts: carrying out alcohol extraction and water extraction on Cortex moutan dregs, carrying out alcohol extraction and water extraction on Ramulus cinnamomi dregs, and carrying out alcohol extraction and water extraction on Radix paeoniae alba, peach kernel, and 51-70% of the Poria cocos; concentrating the alcohol extracts or water extracts separately, combining the concentrated extracts for further concentration to obtain extract, and mixing after spray drying to obtain spray-dried powder; and (e) total mixing: mixing the Poria cocos powder intermediate, the spray-dried powder intermediates of extracts, the paeonol inclusion compound, and the Ramulus cinnamomi volatile oil inclusion compound to obtain the traditional Chinese medicine composition.

2. The method according to claim 1, wherein in step (a), drying the Poria cocos at 70° C. to the moisture content of ≤5.0%, then pulverizing the Poria cocos with a 120-mesh sieve, and taking 45% of the Poria cocos powder.

3. The method according to claim 1, wherein step (b) comprises: collecting the aromatic water in a fourfold to sixfold amount of the Cortex moutan during the steam distillation process; including with β-cyclodextrin specifically comprises: adding β-cyclodextrin to purified water in a 2.7-fold amount of the β-cyclodextrin, stirring well, and heating to 60° C. to obtain a β-cyclodextrin solution; adding paeonol in a ⅙- 1/12 amount of the addition of β-cyclodextrin to ethanol in a fourfold to sixfold amount thereof and then heating to dissolve the paeonol; pouring the hot paeonol solution into the β-cyclodextrin solution; processing the solution with a colloid mill for 30 minutes and then discharging the solution, and resting for 16-24 hours; carrying out by suction filtering, drying at 50° C., pulverizing with a 100-mesh sieve, and mixing to obtain the paeonol inclusion compound.

4. The method according to claim 1, wherein step (c) comprises: adding ethyl acetate during the steam distillation process in 3.5% amount of the Ramulus cinnamom; including with β-cyclodextrin specifically comprises: adding β-cyclodextrin to ethanol in a fourfold to sixfold amount thereof, and stirring well to obtain a suspension; adding the volatile oil in a ⅙- 1/12 amount of the addition of β-cyclodextrin to the suspension, stirring well, processing the solution with a colloid mill for 30 minutes, discharging the solution, resting for 16-24 hours, carrying out by suction filtering, drying at 50° C., pulverizing with a 100-mesh sieve, and mixing to obtain the Ramulus cinnamomi volatile oil inclusion compound.

5. The method according to claim 1, wherein step (d) comprises: feeding the Radix paeoniae alba, the peach kernel, and the 51-70% of the Poria cocos in an order of Radix paeoniae alba at the bottom, peach kernel in the middle, and Poria cocos at the top.

6. A traditional Chinese medicine composition prepared by the method according to claim 1, comprising Ramulus cinnamomi, Poria cocos, Cortex moutan, Radix paeoniae alba, and peach kernel in equal proportions, wherein the traditional Chinese medicine composition further contains paeoniflorin, amygdalin, benzoylpaeoniflorin, cinnamic acid, paeonol, and cinnamic aldehyde, wherein the content of Paeoniflorin accounts for 15 mg/g or above of the traditional Chinese medicine composition, the content of amygdalin accounts for 10 mg/g or above of the traditional Chinese medicine composition, and the content of Paeonol accounts for 10 mg/g or above of the traditional Chinese medicine composition.

7. The traditional Chinese medicine composition according to claim 6, wherein a transfer rate of Pachymic acid from Poria cocos to the traditional Chinese medicine composition is greater than 90%.

8. A medicine, made into a clinically acceptable dosage form, comprising the composition according to claim 6 and a pharmaceutically acceptable excipient.

9. A method of treating or preventing any of the following diseases or conditions: primary dysmenorrhea, secondary dysmenorrhea, dysfunctional uterine bleeding, chronic pelvic inflammatory disease and small intramural uterine fibroids, comprising administering the composition according to claim 6 to a subject in need thereof.

10. The method according to claim 4 wherein the volatile oil is added in a 1/10 amount of the addition of β-cyclodextrin to the suspension.

Description

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

(1) The present invention discloses a composition containing Chinese herbal medicines Ramulus cinnamomi and Poria cocos, and a preparation method and application thereof. Those skilled in the art can learn from the content of the present disclosure to conduct the implementation by appropriately improving the process parameters. In particular, it should be pointed out that all similar substitutions and modifications obvious to those skilled in the art are all deemed to be included in the present invention.

(2) Unless otherwise specified, the medicines, reagents, and instruments used in the technical solutions provided by the present invention can be purchased from conventional channels or markets.

Example 1 Preparation of a Capsule Comprising the Composition of the Present Invention

(3) TABLE-US-00001 1. Standard prescription of the capsule Ramulus cinnamomi 360 g Poria cocos 360 g Cortex moutan 360 g Radix paeoniae alba 360 g Peach kernel 360 g prepared into 1000 granules (0.465 g/granule) 2. Production prescription (400 prescription amount) Ramulus cinnamomi 144 kg Poria cocos 144 kg Cortex moutan 144 kg Radix paeoniae alba 144 kg Peach kernel 144 kg prepared into 400,000 granules (0.465 g/granule) 3. Specific preparation method Pre-processing Pre-processing 1:

(4) 3. Specific Preparation Method

(5) Pre-Processing

(6) Pre-Processing 1:

(7) The Cortex moutan in the above five herbs were rinsed with water for 2 minutes, dried in the air, and cut into decoction pieces of 0.5-1 cm in size for use later;

(8) the rest of the medicinal materials were all pure medicinal materials for use; and

(9) 55% of the prescription amount of Poria cocos decoction pieces were weighed for extraction. Alternatively,

(10) Pre-Processing 2:

(11) The above five herbs were all pure medicinal materials for use; and

(12) 55% of the prescription amount of Poria cocos decoction pieces are weighed for extraction.

(13) (a) Preparation of Poria cocos Intermediate

(14) A sufficient amount of Poria cocos powder was dried at 70° C. to a moisture content of ≤5.0% and then pulverized with a 120-mesh sieve; 30-49% of the prescription amount of Poria cocos powder was taken as the Poria cocos powder intermediate, wherein 45% of the prescription amount of Poria cocos was taken preferably.

(15) (b) Preparation of Paeonol Inclusion Compound

(16) (1) Extraction of Paeonol Aromatic Water

(17) The Cortex moutan decoction pieces were put into a multifunctional extraction tank and subjected directly to steam distillation to extract paeonol. The filter cloth of about 100 meshes was used and the aromatic water in 5-fold amount (720 kg) was collected; the dregs were set aside for use later.

(18) (2) Refining of the Cortex moutan Aromatic Water

(19) The Cortex moutan aromatic water was allowed to rest for 48-72 hours until the aromatic water was completely crystallized; the crystals were filtered with a 200-mesh sieve, and then dried in the shade in the purifying zone to obtain 1.8-2.4 kg of paeonol crystals for use later.

(20) (3) Paeonol Inclusion Compound

(21) β-cyclodextrin was added to purified water in 2.7-fold amount of the β-cyclodextrin, stirred well, and heated to 60° C.; paeonol in an amount 1/10 of the addition of β-cyclodextrin was added to 95% ethanol in 5-fold amount and then heated to be dissolved; the hot paeonol solution was poured into the β-cyclodextrin solution; the solution was processed with a colloid mill for 30 minutes and then discharged and allowed to rest overnight for 16-24 hours; the solution was subjected to suction filtering, drying at 50° C. under normal pressure, pulverizing into 100 meshes, and mixing to obtain 16.0-22.0 kg of the paeonol inclusion compound.

(22) (c) Preparation of Ramulus cinnamomi Volatile Oil Inclusion Compound

(23) (1) Extraction of Ramulus cinnamomi Aromatic Water

(24) The decoction pieces of Ramulus cinnamomi were put into a multifunctional tank and subjected directly to steam distillation to extract volatile oil; in the extraction process, the amount of ethyl acetate which was 3.5% of the amount of the medicinal material was added for extraction, the extraction was carried out for 5 hours, and the aromatic water at the ethyl acetate layer was collected.

(25) (2) Refining of Ramulus cinnamomi Aromatic Water

(26) The aromatic water at the ethyl acetate layer was placed in a separating funnel and rested to separate the upper ethyl acetate layer, the lower layer was extracted with an equal amount of ethyl acetate, the ethyl acetate layers were combined and recovered at 60° C. under reduced pressure until there was no obvious droplet reflux; ethanol in an amount almost same as the crude volatile oil was added to the ethyl acetate layer, the solution was then concentrated at 80° C. until there was no obvious droplet reflux, and then concentrated at 90° C. for 20 minutes to obtain 0.50-0.90 L of pure volatile oil for use later.

(27) (3) Cinnamomi Oil Inclusion Compound

(28) β-cyclodextrin was added to 20% ethanol in 5-fold amount and stirred well to obtain suspension; Cinnamomi oil in an amount 1/10 of the addition of β-cyclodextrin was added to the suspension, the solution was stirred well, processed with a colloid mill for 30 minutes and then discharged and allowed to rest for 16-24 hours; the solution was subjected to suction filtering, drying at 50° C. under normal pressure, pulverizing into 100 meshes, and mixing to obtain 5.0-9.0 kg of the Cinnamomi oil inclusion compound.

(29) (d) Preparation of Spray-Dried Powder Intermediate of Extract

(30) (1) Extraction Process

(31) 1) Extraction on Cortex moutan Dregs

(32) 90% ethanol in 4+3 (volume-to-weight ratio, 576 L+432 L) folds amount was added to the Cortex moutan dregs left after extracting aromatic water from Cortex moutan, the extraction was carried out twice, 2 hours each time (working in the cycling mode for 5 minutes after boiling during each extraction), the extract liquid was filtered, and the filtrate was combined to obtain A1 for use later.

(33) Water in 6+4 (864 L+576 L) folds amount was added to the Cortex moutan dregs, the extraction was carried out twice, 2 hours each time (working in the cycling mode for 5 minutes after boiling during each extraction), and the filtrate was combined to obtain B1 for use later; and the dregs were discarded.

(34) 2) Extraction on Ramulus cinnamomi Dregs

(35) 90% ethanol in 4+3 (volume-to-weight ratio, 576 L+432 L) folds amount was added to the Ramulus cinnamomi dregs left after extracting aromatic water from Ramulus cinnamomi, the extraction was carried out twice, 2 hours each time (working in the cycling mode for 5 minutes after boiling during each extraction), and the filtrate was combined to obtain A2 for use later.

(36) Water in 6+4 (864 L+576 L) folds amount was added to the Ramulus cinnamomi dregs, the extraction was carried out twice, 2 hours each time (working in the cycling mode for 5 minutes after boiling during each extraction), and the filtrate was combined to obtain B2 for use later; and the dregs were discarded.

(37) 3) Extraction on Radix paeoniae Alba, Peach Kernel and 55% of the Prescription Amount of Poria cocos

(38) Radix paeoniae alba, peach kernel, and 55% of the prescription amount of Poria cocos were fed in an order of Radix paeoniae alba at the bottom, peach kernel in the middle, and Poria cocos at the top; 90% ethanol as 4+3 (volume-to-weight ratio, 1468.8 L+1101.6 L) folds as the amount of the medicinal materials was added to perform extraction twice, 2 hours each time (working in the cycling mode for 5 minutes after boiling during each extraction), and the filtrate was combined to obtain A3 for use later.

(39) Water in 6+4 (2203.2 L+1468.8 L) folds amount was added to the dregs, the extraction was carried out twice, 2 hours each time (working in the cycling mode for 5 minutes after boiling during each extraction), and the filtrate was combined to obtain B3 for use later; and the dregs were discarded.

(40) (2) Concentration

(41) 1) Concentration of Alcohol Extract Liquid

(42) The alcohol extract liquids A1, A2, and A3 were combined and concentrated under reduced pressure. The alcohol extract liquid was recovered to a relative density of 1.02-1.05 (70±5° C.) and weighed to obtain the alcohol extract.

(43) 2) Concentration of Water Extract Liquid

(44) The water extract liquids B1, B2, and B3 were combined, and concentrated under reduced pressure to a relative density of 1.05-1.10 (80±5° C.), weighted to obtain a water extract.

(45) 3) Combination and Concentration

(46) The concentrated liquid of the alcohol extract and the concentrated liquid of the water extract were combined, further concentrated to a relative density of 1.15 (80±5° C.), and sieved with a sieve of 80-100 meshes to obtain an extract; the obtained extract was refrigerated for storage or spray dried directly.

(47) (3) Spray Drying Process

(48) 1) Spray Drying

(49) The combined extract was spry dried, the inlet air temperature was set to 165-170° C., and the outlet air temperature was controlled to 90-95° C. during the spray-drying process; the resulting powder was cooled to room temperature, and then discharged, thus obtaining the spray-dried powder.

(50) 2) Mixing of Spray-Dried Powder

(51) The pulverized spry-dried powder was mixed for a time ≥15 minutes, and the spry-dried powder of the extract was finally obtained for use later.

(52) (e) Total Mixing

(53) The Poria cocos, the spray-dried powder, the paeonol inclusion compound, and Cinnamomi oil inclusion compound were mixed together for total mixing for a time ≥30 minutes to obtain the final bulk drug.

(54) (f) Preparation

(55) The bulk drug was dry-granulated (24 meshes), sized, well mixed to obtain granules, 0.465 g/granule; the granules were filled into No. 0 green capsule shells to obtain the finished product.

(56) 4. Comparison of the Preparation Method of the Present Invention with the Method Disclosed in the Prior Art CN200780027994.4

(57) TABLE-US-00002 TABLE 1 Comparison of production efficiency Time of process step Pulverizing of Different Poria Drying processes cocos Extraction Concentration process Pulverizing Inclusion Granulation Total (h) Prior art 8 h 12 h   8 h Poria 10 h 24 h (Soft   98 h cocos material powder powder + 2 was includion mixed compounds) with the wet extract granulation and dried and drying, under the sizing normal process time pressure was 16 hours for 20 hours The method of 5 h 12 h 8.5 h The — 24 h (Extract  67.5 h the present extract powder + 2 invention was inclusion directly compounds + spray Poria dried for cocos 8 hours powder) dry granulation time was 10 hours Improvement −3 0 0.5 −12 −10 0 −6 −30.5 h

(58) It can be seen from Table 1 that the combined extract of the present invention is directly spray-dried to obtain medicinal powder, and the paeonol inclusion compound, Ramulus cinnamomi volatile oil inclusion compound, and Poria cocos powder are directly combined for dry granulation. Compared with the prior art, the present invention reduces the process of drying, pulverizing, wet granulating drying of the Poria cocos mixed extract. The production efficiency of the preparation method in the present invention is improved by 30% or above.

(59) TABLE-US-00003 TABLE 2 Comparison of the content of each index component Indicator component (mg/g) Benzoyl- Cinnamic Different processes Paeoniflorin Amygdalin paeoniflorin acid Paeonol Cinnamaldehyde Prior art 11.29 3.87 — — 6.45 — The method of the present 18.98 15.00 0.85 1.21 12.23 2.12 invention (Batch 1) The method of the present 15.26 13.22 0.80 1.09 11.16 2.02 invention (Batch 2) The method of the present 17.33 14.04 0.91 1.25 12.01 2.25 invention (Batch 3) Improvement Compared with the prior art, the present invention is significantly improved in the contents of the index components

(60) It can be determined from the data in Table 2 that in the preparation of the present invention, the effective ingredients are significantly increased, and the content of each index component is significantly higher than that in the prior art.

(61) TABLE-US-00004 TABLE 3 Comparison of transfer rate of poriaic acid Different Transfer rate % of poriaic acid processes Batch 1 Batch 2 Batch 3 Prior art 60.2 57.8 58.4 The method of the 90.6 91.3 92.5 present invention Improvement Compared with the prior art process, the present process reduces the process of drying, pulverizing, wet granulating drying of the Poria cocos mixed extract, so the transfer rate of poriaic acid is significantly improved.

(62) It can be determined from the data in Table 3 that the present invention reduces the process of drying, pulverizing, wet granulating drying of the Poria cocos mixed extract, and the transfer rate of poriaic acid reaches 90% or above, which is much higher than the transfer rate of poriaic acid in the method used in the prior art.

(63) TABLE-US-00005 TABLE 4 Comparison of products in moisture absorption rate Different Moisture absorption percentage % processes Sample 1 Sample 2 Sample 3 Prior art 3.25 3.04 3.16 The method of the 1.25 1.08 1.21 present invention Improvement The Moisture absorption rate is obviously lower than that the prior art process

(64) From the data in Table 4, it can be determined that in the present invention, since the Poria cocos powder is mixed with three other intermediates during the process of making a preparation to be directly put in dry granulation (no added solvent), the moisture absorption rate of the product is obviously lower than the method used in the prior art by more than 60%.

(65) TABLE-US-00006 TABLE 5 Comparison in the dissolution of each index component in the preparation Dissolution % Different Benzoyl- Cinnamic processes Paeoniflorin Amygdalin paeoniflorin acid Paeonol Cinnamaldehyde Prior art 62.5 59.7 56.3 59.6 62.4 56.4 The method of the 89.6 86.5 88.4 84.8 87.8 90.4 present invention Improvement Compared with the prior art process, the present invention is significantly improved in the dissolution of the index components

(66) It can be determined from the data in Table 5 that in the present invention, because the extract is directly spray dried and combined with other intermediates and then directly made into a preparation, the dissolution of each index component is significantly better than that of the method used in the prior art.

(67) TABLE-US-00007 TABLE 6 Comparison in rationality of preparation process Different Comparison in advantage and disadvantage processes Drying Pulverizing Granulation drying Method The extract is The pulverizing Wet granulation of the mixed with Poria process of the dried takes a long time, prior art cocos powder soft material has high energy and dried: it takes powder causes high consumption and a long time, the noise, high dust high intensity, and is operation production rate and likely to cause technology is environmental pollution. backward, the pollution. labor intensity is high, and it is likely to cause pollution. Method of Direct spray The fine powder of Low time cost, low the present drying of the the medicine can energy consumption, invention extract: it takes a be obtained directly low intensity, and no short time, and through spray pollution. has advanced drying without technology, low pulverizing. labor intensity and no pollution. Improve- The process and operation method are relatively reasonable. ment

(68) It can be determined from Table 6 that the rationality of the preparation process of the present invention is obviously better than that of the method used in the prior art.

(69) It can be seen that the active ingredient content, dissolution rate, moisture absorption rate, the pachymic acid transfer rate, production efficiency, etc., and various process parameters of the composition of the present invention are significantly better than those in the prior art.

(70) It should be noted that those skilled in the art can learn from the content of the present disclosure to conduct the implementation by appropriately improving the process parameters. All similar replacements and modifications obvious to those skilled in the art are considered to be included in the present invention.