CN101185653B - Breviscapine oral administration composition and preparation method thereof - Google Patents

Abstract

The invention belongs to the field of pharmaceuticals, and relates to an oral composition of breviscapine and a preparation method thereof. The present invention is composed of breviscapine, fatty acid triglycerides, fatty acid monoglycerides or fatty acid diglycerides or a mixture of the two in any proportion and a surfactant, wherein scutellarin can be suspended in the composition in any proportion middle. Experiments have confirmed that the digestive ester hydrolysis product of the oral composition can promote the increase of intestinal mucosal permeability and solubility of scutellarin, and in vivo experiments show that it can improve the intestinal absorption bioavailability of scutellarin. The breviscapine oral composition of the present invention is made into solid dosage forms such as soft capsules, hard capsules, pellets or tablets, or enteric-coated forms of these dosage forms. The invention has the advantages of simple preparation, low toxicity, good storage stability and the like.

Description

Breviscapine oral composition and preparation method thereof

technical field

The invention belongs to the field of pharmaceutical preparations, and relates to an oral composition of scutellarin and a preparation method thereof.

Background technique

Brevescapine (Brevescapine) is a class of flavonoids isolated from the Compositae breviscapus (formerly known as breviscapus, also known as breviscapus, Erigeron Breviscapus), mainly containing scutellarin (Scutellarin, chemical name 4 ', 5,6-trihydroxyflavone-7-glucuronide). Pharmacodynamic studies have shown that breviscapine can expand cerebral blood vessels, reduce cerebral vascular resistance, increase cerebral blood flow, improve microcirculation, and increase the permeability of the blood-brain barrier. Breviscapine is widely used clinically to treat cerebral thrombosis, cerebral infarction, and post-stroke paralysis of undetermined type.

The commercial preparations of breviscapine include breviscapine injection, breviscapine injection, breviscapine tablet, and breviscapine granule. Although breviscapine injection has fast absorption and high bioavailability, the patient's compliance is poor, and the steps of preparation, packaging, transportation and storage are relatively complicated; breviscapine is a flavonoid compound, and its water solubility and fat solubility are very poor , the absorption bioavailability of its oral preparations is extremely low, and it is reported that the oral bioavailability of breviscapine tablets is only 0.40±0.19% (Ge Qinghua et al., Pharmacokinetics and Absolute Bioavailability of Breviscapine in Dogs, Chinese Medicine Journal of Industry, 2003, 34(12): 618-620). FDA (US Food and Drug Administration) believes that the biopharmaceutical properties that determine the oral absorption of drugs are mainly drug solubility and mucosal permeability, and based on this standard, drugs are divided into categories I, II, III and IV. Breviscapine belongs to IV drugs, that is, drugs with low solubility and low mucosal permeability, and the oral bioavailability of such drugs is often low. Therefore, the key factors to improve the oral bioavailability of breviscapine should be to improve its solubility and intestinal mucosal permeability.

Most of the breviscapine oral preparations disclosed in the prior art lack targeted means to solve the above-mentioned defects of breviscapine at the same time, and some disclosed technologies are only simple changes in oral dosage forms, such as orally disintegrating tablets (CN1695629A; CN1698638A; CN1429618A ；CN1582955A)、分散片(CN1530113A；CN1416817A)、缓释或控释制剂(CN1233327C；CN1212114C；CN1205940C；CN1172679C；CN1480147A；CN1530114A；CN1565472A；CN1515264A)、舌下片(CN1634105A)、软胶囊(CN1069520C)等； Some use new preparation techniques to improve the solubility or dissolution of breviscapine, such as preparing dropping pills (CN1565471A; CN1480148A; CN1408392A; CN1768763A; CN1437950A; CN1531929A; CN1444947A); using solid dispersion technology (CN1102392C); nanotechnology (CN1364516A) ; Adopt cyclodextrin inclusion technology (CN1739537A); Adopt self-emulsification technology (CN1593449A), but the surfactant and co-surfactant in the disclosed self-emulsification preparation are as high as 80% (optimal choice), may cause gastrointestinal Toxic and side effects of breviscapine; in terms of increasing breviscapine mucosal permeability, there are few literature and patent reports at present, only breviscapine phospholipid complex (CN1359682A) is disclosed, and the strong lipophilicity of phospholipids is used to increase the breviscapine in the complex. Floridin has membrane permeability, but its preparation is complicated, its stability is not good, and the price of phospholipid is relatively expensive, which is not good for production or cost control.

To sum up, to solve the problem of oral absorption bioavailability of breviscapine, targeted measures should be taken based on its poor biopharmaceutical properties.

Contents of the invention

The purpose of the present invention is to provide a scutellarin oral composition and a preparation method thereof that can effectively increase the oral bioavailability of scutellarin.

The invention achieves the purpose of improving the oral bioavailability of the breviscapine through increasing the mucosal permeability and solubility.

The scutellarin oral composition provided by the invention is composed of scutellarin, fatty acid triglyceride, fatty acid monoglyceride or fatty acid diglyceride or a mixture of the two in any proportion and a surfactant.

M1944、Labrafil

M2125、Plurol

Oleique CC497、Gelucire

33/01(Gattefosse)等，可选用的中链三甘酯，碳链为C₈-C₁₀，商品名可以是Miglycol

812N(Sasol)、Captex

355EP、Captex

350、Captex

300EP(Abitec)等，也可以选用上述油以任何比例的混合物。优选碳链为C₈-C₁₀的中链三甘酯。Fatty acid triglyceride of the present invention, carbon chain is C6-C18, saturated or unsaturated all can, wherein the long-chain triglyceride of selection can be the corn oil (Maisine) of soybean oil, corn oil or acyl transfer, Labrafil

M1944, Labrafil

M2125, Plurol

Oleique CC497, Gelucire

33/01 (Gattefosse), etc., the optional medium-chain triglyceride, the carbon chain is C ₈ -C ₁₀ , the trade name can be Miglycol

812N (Sasol), Captex

355EP, Captex

350、Captex

300EP (Abitec), etc., can also choose the mixture of the above oils in any proportion. Medium chain triglycerides with carbon chains of C ₈ -C ₁₀ are preferred.

988(Sasol Corp.)、Capmul

MCM C8(Abitec Corp.)等，C₈-C₁₀单/二甘酯的商品名有Imwitor

742(SasolCorp.)、CapMum

MCM(Abitec Corp.)、Capmul

MCM C10(Abitec Corp.)、Labrafac

CC(Gattefosse)等；The fatty acid monoglyceride, the fatty acid diglyceride or the mixture thereof in any proportion has a carbon chain of C6-C18, which can be saturated or unsaturated. Preferred carbon chains are C ₈ -C ₁₀ monoglycerides, diglycerides or mono/diglycerides, where the trade name of commonly used C8 monoglycerides is Imwitor

988 (Sasol Corp.), Capmul

MCM C8 (Abitec Corp.), etc., the trade name of C ₈ -C ₁₀ mono/diglycerides is Imwitor

742 (Sasol Corp.), CapMum

MCM (Abitec Corp.), Capmul

MCM C10 (Abitec Corp.), Labrafac

CC (Gattefosse), etc.;

Described tensio-active agent can select following one or more for selection:

1. Polyoxyethylene sorbitan fatty acid esters (such as trade name Tween), including the following products: polyoxyethylene sorbitan monolaurate (Tween 20), polyoxyethylene sorbitan monopalmitate (Tween40), polyoxyethylene sorbitan monostearate (Tween 60), polyoxyethylene sorbitan monooleate (Tween 80), polyoxyethylene sorbitan trioleate (Tween 85);

2. Polyoxyethylene fatty alcohol ethers (such as trade name Brij, Benzze), preferably this type of product is Brij 35;

3. Polyoxyethylene fatty acid esters (such as trade name Myrj, sold Ze), preferably this type of product is Myrj 52;

4. Ethylene oxide-propylene oxide block copolymer (such as trade name Pluronic, poloxamer), preferably such products are Pluronic F68 (poloxamer 188);

5. Polyethylene glycol hydrogenated castor oil (for example, trade name Cremophor RH40) or polyethylene glycol castor oil (Cremophor EL);

6. Vitamin E polyethylene glycol succinate (TPGS), commercially available from Eastman Fine Chemical Company);

7. Polyethylene glycol-8-glycerol caprylic acid/capric acid ester (such as trade name Labrasol, Gattefosse);

9. Phospholipids, including lecithin and soy lecithin.

Preferred surfactants are Cremophor EL, Tween 80, TPGS and Labrasol.

The scutellarin oral composition of the present invention is characterized in that the ratio of fatty acid monoglyceride or fatty acid diglyceride or a mixture of the two to fatty acid triglyceride and surfactant is 1:0.2～6:0.2～2, preferably The ratio is 1:1-4:0.4-1, the most preferred ratio is 1:3:0.5.

The present invention prepares breviscapine oral composition through the following method:

Firstly, after mixing fatty acid monoglyceride or fatty acid diglyceride or a mixture of the two and surfactant evenly, add scutellarin and stir evenly, finally add fatty acid triglyceride and stir evenly to obtain the scutellarin oral composition of the present invention things. A small amount of scutellarin is dissolved in the composition, while most of it is in a suspended state, and scutellarin can be suspended in the composition in any proportion;

Enteric-coated hard capsules, enteric-coated soft capsules and other preparations can be obtained by filling the above-mentioned prepared composition into hard capsules, soft capsules, and enteric-coated hard capsules, or performing enteric-coating after filling the capsules;

The above-mentioned prepared composition is adsorbed by a solid carrier such as silicon dioxide, calcium sulfate, dextrin or cross-linked polyvinylpyrrolidone to form a solid powder, which is then made into granules or pellets, and then further prepared into tablets and capsules , granules, etc. or enteric-coated forms of said preparations.

The oral composition of the present invention has been subjected to in vitro digestion experiments, intestinal sac reversal experiments, solubility experiments and in vivo absorption experiments, and the results have confirmed that it can improve the permeability of scutellarin through the intestinal mucosa and increase the solubility of breviscapine in the gastrointestinal tract. and dissolution rate, and significantly improve the intestinal absorption bioavailability of scutellarin. The present invention aims at the poor oral biopharmaceutical properties of scutellarin, solves the defects in the prior art, and realizes that the gastrointestinal absorption can be improved in the gastrointestinal tract. The permeability of the mucous membrane and the effect of increasing the solubility and dissolution rate can significantly improve the intestinal absorption bioavailability of breviscapine, and at the same time, it has the advantages of simple and convenient preparation, low toxicity and good storage stability.

Description of drawings

Fig. 1 is the in vitro digestion curve of breviscapine oral composition.

Fig. 2 is a diagram of the blood drug concentration-time curve (n=4) of the breviscapine composition absorbed through the duodenum.

Fig. 3 is a micrograph of the tissue section of the intestinal mucosa after duodenal administration of the oral composition.

Among them, A is a section view of a breviscapine saline suspension in the control group, and microscopic observation shows that the villi remain intact and do not fall off;

B shows that after the duodenum is administered with Example 4, the small intestinal villi are similar to those of the control group, without damage;

C shows that after the duodenum is administered with Example 5, the villi of the small intestine become slightly shortened and fall off, but the villi generally maintain a relatively complete form;

D is the positive control group, that is, the duodenum was given 0.1% triton, and the microscopic observation of the small intestine showed that the villi of the small intestine were seriously fused and fell off.

Detailed ways:

Example 1

Labrafac CC 3.13g

Maisine 0.63g

Cremophor EL 6.25g

Breviscapine 0.4g

 CC和Cremophor EL，混合均匀，在不断搅拌下加入灯盏花素，最后再加入Maisine，搅拌均匀即得。During preparation, weigh Labrafac according to the above prescription amount

CC and Cremophor EL, mix evenly, add scutellarin under constant stirring, and finally add Maisine, stir evenly.

Example 2

988    1.39gImwitor

988 1.39g

M1944 8.33gLabrafil

M1944 8.33g

Brij35 0.28g

Breviscapine 0.4g

988和Brij 35，混合均匀，在不断搅拌下加入灯盏花素，最后再加入Labrafil

M1944，搅拌均匀即得。During preparation, weigh Imwitor according to the above prescription amount

988 and Brij 35, mix well, add breviscapine with constant stirring, and finally add Labrafil

M1944, stir evenly.

Example 3

MCM     4.00gCapMum

MCM 4.00g

350     4.00gCaptex

350 4.00g

Phospholipids 2.00g

Breviscapine 0.4g

MCM和磷脂，混合均匀，在不断搅拌下加入灯盏花素，最后再加入Captex

350，搅拌均匀即得。During preparation, weigh CapMum according to the above prescription amount

MCM and phospholipids, mix well, add breviscapine with constant stirring, and finally add Captex

350, stir well and serve.

Example 4

742    1.67gImwitor

742 1.67g

Miglycol812N 6.67g

Tween80 1.67g

Breviscapine 0.4g

742和Tween80，混合均匀，在不断搅拌下加入灯盏花素，最后再加入Miglycol812N，搅拌均匀即得。During preparation, weigh Imwitor according to the above prescription amount

742 and Tween80, mix evenly, add scutellarin under constant stirring, and finally add Miglycol812N, stir evenly to get the product.

Example 5

MCM C10 2.22gCapmul

MCM C10 2.22g

Miglycol812N 6.67g

TPGS 1.11g

Breviscapine 0.04g

MCM C10和TPGS，混合均匀，在不断搅拌下加入灯盏花素，最后再加入Miglycol812N，搅拌均匀即得。When preparing, according to the above prescription amount, weigh Capmul

Mix MCM C10 and TPGS evenly, add breviscapine under continuous stirring, and finally add Miglycol812N, stir evenly to get ready.

Example 6

CapMum MCM 1.25g

742    1.25gImwitor

742 1.25g

soybean oil 5.00g

Cremophor EL 2.50g

Breviscapine 0.4g

MCM、Imwitor

742和CremophorEL，混合均匀，在不断搅拌下加入灯盏花素，最后再加入大豆油，搅拌均匀即得。When preparing, according to the above prescription amount, weigh Capmul

MCM, Imwitor

742 and CremophorEL, mix evenly, add scutellarin under continuous stirring, and finally add soybean oil, stir evenly.

Example 7

988    3.33gImwitor

988 3.33g

355     3.33gCaptex

355 3.33g

Cremophor EL 1.67g

Labrasol 1.67g

Breviscapine 0.4g

988、Cremophor EL和Labrasol，混合均匀，在不断搅拌下加入灯盏花素，最后再加入Captex

355，搅拌均匀即得。During preparation, weigh Imwitor according to the above prescription amount

988, Cremophor EL and Labrasol, mix well, add breviscapine under constant stirring, and finally add Captex

355, stir well and serve.

Example 8

The breviscapine oral composition prepared in Example 2 was used as a matrix to prepare soft capsules, wherein each soft capsule contained 20 mg breviscapine.

Example 9

The breviscapine oral composition prepared in Example 5 is directly enema-coated into hard capsules, wherein each capsule contains 20 mg breviscapine.

Example 10

Weigh 10 g of the breviscapine oral composition prepared in Example 4, and add 5 g of micropowdered silica gel successively in the grinding state to obtain a solid powder of the breviscapine oral composition. The angle of repose of the powder is determined to be 39.5°. The density is 0.54g/cm ³ .

Example 11

The breviscapine oral composition solid powder prepared in Example 10 was filled into No. 0 capsules, and the capsules were coated with the enteric coating material Eudragit L100-55 in a high-efficiency coating pan to obtain breviscapine enteric-coated capsules. Each capsule contains breviscapine 20mg or 40mg.

Example 12

Example 1 100g

Microcrystalline Cellulose 120g

Distilled water 36g

Ethanol 18g

When preparing scutellarin oral composition pellets, weigh microcrystalline cellulose, add distilled water and ethanol successively, knead evenly, and then add the scutellarin composition prepared in Example 1 to make a soft material. After the prepared soft material is sealed for 1.5 hours, pellets are prepared by extrusion and spheronization equipment, and the particle size is between 16 and 24 meshes, accounting for more than 85%. Coat the pellets with enteric coating material Eudragit L100-55 in a fluidized bed for 1 hour, continue to dry for 0.5 hour, take them out, and heat them at 45-50°C for 12 hours to prepare scutellarin pellets. Fill the pellets into No. 0 capsules, and each capsule contains 20mg or 40mg of breviscapine.

Example 13

Example 6 30%

Maltodextrin 15%

Cross-linked polyvinylpyrrolidone 15%

Microcrystalline Cellulose 40%

When preparing breviscapine oral composition tablets, weigh the breviscapine composition prepared in Example 6, add maltodextrin and cross-linked polyvinylpyrrolidone successively under stirring state, and cure completely, and measure the angle of repose to be 38.5 °, then add microcrystalline cellulose, mix evenly, and directly press the powder into tablets to obtain breviscapine tablets, each containing 20 mg breviscapine.

Example 14 In vitro digestion experiment

In order to explore the in vivo digestion behavior of the oil in the oral composition of breviscapine and the effect of its digested esterification products on the permeability of scutellarin mucosa, an in vitro digestion model was established according to the relevant physiological parameters of the digestive system in vivo as follows:

First prepare a buffer, which consists of 50mM tris-maleic acid (Trizma maleate), 150mM NaCl and 5mM Ca ²⁺ , adjust the pH to 6.8; then use the buffer to prepare a bile salt micellar solution (by 5mM Sodium taurodeoxycholate and 1.25mM phosphatidylcholine form); When the digestion experiment started, the bile salt micellar solution of 9ml was mixed with the oral composition of 0.5g-embodiment 4 and embodiment 5 (the two did not contain Breviscapine) or 0.5g of the control group (Miglycol 812N) were mixed and stirred evenly, then 1ml of trylipase solution (concentration: 1000U/ml) was added, timed immediately and titrated with 0.2M NaOH to maintain the pH of the whole system at 6.8, at different times See Figure 2 for the percentage of oil digestion and esterification plotted.

The results showed that, compared with the control group, Example 4 and Example 5 could be digested rapidly, and the esterolysis rate reached about 65% in 5 minutes, while that of the control group was 40%. The esterification products of the oral composition, such as fatty acid sodium, fatty acid monoglyceride and bile salt phospholipid, form complex mixed micelles, thereby effectively promoting the penetration of breviscapine through the intestinal mucosa.

Example 15 Flip the intestinal sac experiment

Rats were fasted overnight (with free access to water), and anesthetized with 20% urethane (1 g/kg) by intraperitoneal injection. After cutting the abdominal cavity along the midline of the abdomen, take out the jejunum segment of 6-7 cm, place it in ice-cold Tyrode's solution, inject oxygen, and cut off the mesentery. Use a glass tube with an outer diameter of 2.5 mm to gently turn the intestinal segment so that the intestinal mucosa faces outward and the serosa side faces inward. The anal end of the intestine is ligated, and the upper end of the intestinal pouch is fixed at the sampling port. Inject blank Tyrode's solution into the intestine from the sampling port as the receiving solution. Add K ⁺ , glucose, etc. to the liquid after digestion and esterification in Example 14 to make the composition of the benchtop liquid approximately the same, prepare the concentration of scutellarin to 500ng/ml, and prepare the same concentration of scutellarin with pH 6.8 phosphate buffer solution The scutellarin solution was used as the control group, and the above solution was used as the supply solution for the flipping intestinal sac experiment to investigate the mucosal permeability of scutellarin. At 15, 30, 45, 60, and 90 min, 0.6 ml was sampled from the intestinal sac, centrifuged at 10,000 rpm for 10 min, and 0.4 ml of the clear liquid was used to measure the concentration of breviscapine by HPLC, and the same volume of isothermal Tyrode's solution was added at the same time.

The cumulative permeation percentage and increase multiple of breviscapine after 1.5 hours of flipping the intestinal sac test are shown in Table 1. The results show that after the oral composition of the present invention is digested and esterified in the intestinal tract, the esterification product of the breviscapine significantly promotes breviscapine. Permeabilization of mucous membranes.

Table 1. Cumulative penetration percentage and increase multiple of breviscapine through rat jejunum

preparation   Cumulative transmission percentage (%)   Multiplier Control group Example 4 Digestion product Example 5 Digestion product 6.15±1.0215.23±2.5418.41±3.06 12.53.0

Embodiment 16 Solubility experiment

Weigh the excess scutellarin, put it in the pH6.8 PBS solution and the digested solution of Example 14, shake at a constant temperature of 37°C for 10 hours, centrifuge at a high speed for 10 minutes, take the supernatant, and measure it by HPLC. Table 2. The results show that the digestion products of the breviscapine oral composition can significantly increase the solubility of breviscapine.

Table 2. Solubility of scutellarin in different media

media Solubility (mg/ml) Multiplier pH6.8PBS Example 4 Digestion Product Example 5 Digestion Product 7.23±0.4516.52±2.5621.85±3.55 12.283.02

Example 17 In vivo absorption experiment of breviscapine oral composition

Take 16 SD rats with a body weight of 250g-280g, fast overnight (free drinking water), inject chloral hydrate (6.5%) solution 1ml/100g into the abdominal cavity after weighing, fix their backs on the operating table after anesthesia , for carotid artery cannulation for blood. The rats were randomly divided into 4 groups, one group was intraperitoneally injected with breviscapine solution at a dose of 10 mg/kg; the other three groups were cut open along the midline of the abdomen, and the preparations of breviscapine in each group were administered to the duodenum, respectively. Group-breviscapine suspension (prepared with physiological saline), Example 5 and Example 10, the doses are 80 mg/kg. 0.3 ml of blood was collected from each group above at different times before and after administration, added to a plastic centrifuge tube containing heparin, centrifuged at 6,000 rpm for 10 minutes, and the plasma was taken and stored in a refrigerator at -20°C.

The chromatographic conditions for HPLC determination of breviscapine blood concentration are: Shimadzu LC-10AD high performance liquid chromatography system; SPD-10A ultraviolet detector; chromatographic column is Phenomenex Luna C ₁₈ (250mm×4.60mm, 5 μm); mobile phase is Acetonitrile: 0.2% phosphate buffer solution (22:78); the flow rate is 1 ml/min; the detection wavelength is 335 nm; the AUFS is 0.002, the column temperature is 40° C., and the injection volume is 30 μl.

Precisely draw the plasma sample back to room temperature, add an equal volume of methanol, vortex for 20s, centrifuge at 6000rpm for 10min, separate the supernatant, and directly inject the sample for quantification with external standard method. The equation of the standard curve is: concentration C (μg/ml) = 1.18*10 ^-5 A + 0.082 (r = 0.9993), and the linear range is 0.1-10 μg/ml. The intraday precision of the determination of high, medium and low blood levels of breviscapine was 5.94%, 3.82% and 2.92%, and the interday precision was 6.90%, 5.32% and 6.69%, respectively. The specificity of the method met the requirements, and the impurities in the plasma did not interfere with the determination of breviscapine.

Example 18

According to the experimental method of Example 17, the blood drug concentration-time curve of scutellarin duodenum absorption is shown in Figure 2, and the average pharmacokinetic parameters are shown in Table 3, wherein C _max and T _max are measured values, and AUC is calculated by trapezoidal method . The bioavailability of breviscapine preparations in the duodenum was calculated using intraperitoneal injection of breviscapine as a control. The results showed that the absorption of the control group-breviscapine suspension was poor, and the bioavailability was only 2.40%. Compared with the control group, the absorption of breviscapine in Example 5 and Example 10 increased significantly. Compared with the AUC of intraperitoneal injection, the bioavailability was 38.07% and 35.18%, respectively, which was 15.9 times and 15.9 times higher than that of the control group. 15.0 times.

The oral composition of the present invention can significantly improve the intestinal absorption bioavailability of breviscapine, and the reason may be that its digested ester hydrolysis product can promote the increase of cell membrane fluidity, reduce the viscosity of the mucus layer, etc., which is beneficial to the intestinal penetration of breviscapine, and at the same time It can also increase the solubility of breviscapine and facilitate its passive diffusion through the intestinal mucosa. The above-mentioned comprehensive factors promote the increase of the absorption of breviscapine.

Table 3. Pharmacokinetic parameters of breviscapine composition absorbed in duodenum in vivo (n=4)

dosage form Tmax(h) Cmax(ug/ml) AUC(ug.h/ml) F(%) doubled Example 5 Example 10 Control group intraperitoneal injection 0.250.56 6.37±1.234.62±1.020.48±0.15 19.67±2.3121.34±2.121.23±0.255.58 38.07±3.3635.18±3.812.40±1.70100% 15.8614.991

Example 19

According to the experimental method of Example 17, after the blood was collected from the duodenum administration groups, the rats were anesthetized with ether until dead, the duodenum section was cut, washed with pH6.8 PBS, and then placed in paraformaldehyde solution In the process, paraffin sections were made, stained with hematoxylin and eosin, and the changes of small intestinal villi were observed under an optical microscope. The results are shown in Figure 3. Fig. 3A is a section view of the control group-breviscapine saline suspension. Microscopic observation shows that the villi remain intact and do not fall off; Injury; Figure 3C shows that the small intestinal villi slightly shortened and fell off after the duodenum was given Example 5, but the villi remained in a relatively complete shape overall; Figure 3D is a positive control group designed separately, that is, the duodenum administered 0.1% Triton, sliced and observed that the small intestinal villi were seriously fused and shed. Experiments show that the breviscapine oral composition of the present invention has almost no toxicity to the small intestinal mucosa, and can maintain the integrity of the small intestinal villi.

Claims (10)

1. A breviscapine oral composition is characterized in that it is composed of breviscapine, fatty acid monoglyceride or fatty acid diglyceride or a mixture of the two in any proportion, fatty acid triglyceride and surfactant; the fatty acid The ratio of monoglyceride or fatty acid diglyceride or the mixture of the two to fatty acid triglyceride and surfactant is 1:0.2～6:0.2～2. 2. The breviscapine oral composition according to claim 1, characterized in that the ratio of the fatty acid monoglyceride or fatty acid diglyceride or the mixture of the two to the fatty acid triglyceride and the surfactant is 1: 1~4: 0.4~1. 3. The breviscapine oral composition according to claim 1, characterized in that the ratio of the fatty acid monoglyceride or fatty acid diglyceride or the mixture of the two to the fatty acid triglyceride and the surfactant is 1: 3:0.5. 4. The breviscapine oral composition according to claim 1, characterized in that the fatty acid monoglyceride, fatty acid diglyceride or a mixture of the two in any proportion has a carbon chain of C ₆ -C ₁₈ . 5. The breviscapine oral composition according to claim 1 or 4, characterized in that the fatty acid monoglyceride, fatty acid diglyceride or a mixture of the two in any proportion has a carbon chain of C ₈ -C ₁₀ medium chain monoglycerides, diglycerides or mono/diglyceride blends. 6. The breviscapine oral composition according to claim 1, characterized in that the fatty acid triglyceride has a carbon chain of C ₆ -C ₁₈ . 7. The breviscapine oral composition according to claim 1 or 6, characterized in that the fatty acid triglyceride is a medium-chain triglyceride with a carbon chain of C ₈ -C ₁₀ . 8. The breviscapine oral composition according to claim 1, characterized in that the surfactant is selected from polyoxyethylene sorbitan fatty acid esters, polyoxyethylene fatty alcohol ethers, polyoxyethylene fatty acids Esters, ethylene oxide-propylene oxide block copolymers, macrogol natural or hydrogenated castor oil, macrogol vitamin E succinate, macrogol-8-glyceryl caprylate/caprate, phospholipids, or the above mixture of surfactants. 9. The oral composition of breviscapine according to claim 8, characterized in that the surfactant is polyethylene glycol natural or hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, vitamin succinate E macrogol ester or macrogol-8-glyceryl caprylate/caprate. 10. The preparation method of the oral composition of scutellarin according to claim 1, characterized in that it comprises the following steps: after uniformly mixing fatty acid monoglyceride or fatty acid diglyceride or a mixture of the two and surfactant , add breviscapine, stir evenly, add fatty acid triglycerides and stir evenly to obtain breviscapine oral composition.

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