CN105796518B - A kind of diosbulbin B dispersible tablet and preparation method thereof - Google Patents

Abstract

The present invention relates to a dispersible tablet of acetaminophen B, which is composed of the following percentages by weight: 2.5-5.0% of acetaminophen B, 5-15% of cross-linked hydroxymethyl starch sodium as a disintegrating agent, 0.5-3.0% of micropowdered silica gel as a wetting agent, and 0.5-3.0% of micronized Crystalline cellulose 20-40%, the balance is cellulose lactose. At the same time, it also involves the preparation method of dispersible tablets of luteolin B. The wet granulation method is adopted, and the disintegrating agent is added by internal and external addition. ‑3/4 mixing and granulation, then adding micropowder silica gel and the remaining cross-linked sodium hydroxymethyl starch, and compressing into tablets to obtain dispersible tablets. The invention improves the bioavailability of the lutein B, increases the disintegration rate and dissolution rate of the drug, has small adverse reactions and has good stability.

Description

A kind of yellow sole B dispersible tablet and preparation method thereof

technical field

The invention belongs to the technical field of medicines, and in particular relates to a dispersible tablet of yellow sole B and a preparation method thereof.

Background technique

Huangyaozi is the tuber of Dioscorea genus Dioscorea in the Dioscoreaceae family. It has the effects of dispelling stagnation and eliminating galls, detoxifying, reducing swelling, cooling blood and stopping bleeding. It is mostly used clinically to treat various cancers, goiter, cough and asthma, etc. Fenugreek also has antiviral and antibacterial effects. Clinically, it is often compatible with angelica to increase the anti-tumor effect of xanthophyll by reducing the expression of P-glycoprotein.

Xanthophyllin B is an important part of the diterpene lactones in Xanthophyllum officinalis. Flatin B has a dose-dependent anti-tumor effect in the range of 2-16 mg/kg, and has no significant toxicity. Flavor B has obvious inhibitory effect on the proliferation and metastasis of gastric cancer cell SGC-7901, and Flatin B shows SGC -7901 has low cross-drug resistance, which overcomes the disadvantages of chemotherapy drugs with the same mechanism of action that the inhibitory effect of other chemotherapy drugs on the tumor will be reduced to a certain extent after the tumor becomes resistant to a certain chemotherapy drug. However, due to its poor water solubility and low bioavailability, its development and application are limited, and the preparations related to lutein B have not been marketed at home and abroad. Therefore, it will have high application value and broad market prospect to study the appropriate dosage form of lutein B and improve the bioavailability.

Contents of the invention

In order to solve the above problems, the present invention provides a dispersible tablet of lutein B, which improves the bioavailability of lutein B, increases the disintegration rate and dissolution rate of the drug, has less adverse reactions, and has better stability.

The invention also provides a preparation method of the yellow sole B dispersible tablet.

The present invention is achieved through the following technical solutions:

A dispersible tablet of luteolin B, consisting of the following weight percentages: 2.5-5.0% of lutein B, 5-15% of cross-linked hydroxymethyl starch sodium as a disintegrating agent, 0.5-3.0% of micro-powdered silica gel as a wetting agent, and microcrystalline cellulose 20-40%, the balance is cellulose lactose. The cross-linked sodium hydroxymethyl starch is added by internal and external addition, and the ratio of the internally added mass to the externally added amount is 3:1.

Preferably, the dispersible tablet is added with an ethanol solution of 4-6% by mass of the dispersible tablet, and the mass fraction of the ethanol solution is 70%.

Preferably, the yellow sole B dispersible tablet is composed of the following weight percentages, yellow sole B 3.13%, cross-linked hydroxymethyl starch sodium 7.5%, micropowder silica gel 1.13%, microcrystalline cellulose 35%, cellulose lactose 53.24%.

The preparation method of the above-mentioned yellow sole B dispersible tablet adopts the wet granulation method, and the disintegrant adopts the internal and external addition method to add, comprising the following steps:

(1) Weigh and weigh luteolin B, microcrystalline cellulose, cellulose lactose, cross-linked sodium hydroxymethyl starch, and micropowder silica gel according to the weight ratio, and grind them separately, pass through a 100-mesh sieve, and set aside;

(2) Mix 1/2-3/4 of the mass of lutein B, microcrystalline cellulose, cellulose lactose, and cross-linked hydroxymethyl starch sodium in step (1) evenly by using the method of equal increase, and prepare with 70% ethanol For soft materials, pass through a 20-mesh sieve to granulate, dry in an oven at 55°C-60°C to constant weight, pass through a 20-mesh sieve for granulation;

(3) Then add micropowder silica gel and the remaining cross-linked sodium hydroxymethyl starch, mix well, and press into tablets to obtain dispersible tablets with a weight of 0.2±0.01g.

Preferably, the mass of cross-linked sodium hydroxymethyl starch added in step (2) is 3/4 of the mass of cross-linked sodium starch glycolate in step (1).

Beneficial effects of the present invention:

1. The present invention adds adjuvant powder B to make dispersible tablets, which increases the disintegration rate and dissolution rate of the drug, has small adverse reactions, and has good stability under high temperature, high humidity and accelerated constant temperature conditions.

2. Cross-linked hydroxymethyl starch sodium is used as a disintegrant, using internal and external addition, the disintegration time limit is short, the in vitro dissolution rate is high, and the dissolution rate is fast; as a filler, microcrystalline cellulose not only has good compressibility and fluidity It also has dual functions of disintegrant and suspending agent; as a lubricant, micronized silica gel helps to increase the fluidity of granules or powders, because of its silanol-based structure, it can help the disintegration and Dissolution rate.

3. The hardness of the dispersible tablet is 40-60N, and there is enough porosity to achieve the purpose of rapid disintegration, so as to ensure that the tablet has a suitable hardness and has a good appearance and smoothness.

Detailed ways

Drug: Huangdusu B (prepared by Shandong Provincial Traditional Chinese Medicine New Preparation Engineering Center, purity: 99.5%).

Excipients: cellulose lactose (batch number: L1432, Guangzhou Tianrun Pharmaceutical Co., Ltd.); croscarmellose sodium starch (cCMS-Na, batch number: 0011163109, Shanghai Houcheng Fine Chemical Co., Ltd.); microcrystalline cellulose ( Batch number: 20120306, Shanghai Fenghong Pharmaceutical Co., Ltd., pharmaceutical grade).

Example 1

(1) Weigh 2.5g of lutein B, 20g of microcrystalline cellulose, 70.5g of cellulose lactose, 5.0g of cross-linked sodium hydroxymethyl starch, and 2g of micropowdered silica gel according to the weight ratio, and grind them separately, and pass through 100 meshes sieve, spare;

(2) Mix 2.5g of luteolin B, 20g of microcrystalline cellulose, 70.5g of cellulose lactose, and 2.5g of cross-linked hydroxymethyl starch sodium in equal increments, add 4g of soft material made of 70% ethanol, and pass Granulate with a 20-mesh sieve, dry in an oven at 55°C to constant weight, pass through a 20-mesh sieve for granulation;

(3) Then add micropowder silica gel and 2.5g cross-linked sodium hydroxymethyl starch, mix well, and press into tablets to obtain dispersible tablets, each weighing 0.20±0.01g.

Example 2

(1) Weigh 2.5% of lutein B, 20% of microcrystalline cellulose, 70.5% of cellulose lactose, 5.0% of cross-linked sodium hydroxymethyl starch, and 2% of micropowdered silica gel in proportion by weight, and grind them separately, and pass through 100 Mesh sieve, spare;

(2) Mix luteolin B, microcrystalline cellulose, cellulose lactose, and 3.75% cross-linked hydroxymethyl starch sodium in equal increments, and add 70% ethanol containing 6% of the total mass of traditional Chinese medicine in step (1). For soft materials, pass through a 20-mesh sieve to granulate, dry in an oven at 60°C until constant weight, pass through a 20-mesh sieve to granulate;

(3) Then add micropowder silica gel and the remaining 1.25% of cross-linked sodium hydroxymethyl starch, mix well, and press into tablets to obtain dispersible tablets, each weighing 0.20±0.01g.

Example 3

A yellow sole B dispersible tablet, the raw material composition is: 2.5% yellow sole B, 20% microcrystalline cellulose, 65.5% cellulose lactose, 10% cross-linked sodium hydroxymethyl starch, 2% micropowder silica gel. The internal addition amount of cross-linked hydroxymethyl starch sodium is 6.0%, and the external addition amount is 4.0%.

The preparation method is the same as in Example 2.

Example 4

A yellow sole B dispersible tablet, the raw material composition is: 2.5% yellow sole B, 20% microcrystalline cellulose, 60.5% cellulose lactose, 15% cross-linked hydroxymethyl starch sodium, 2% micropowder silica gel. The added amount of cross-linked hydroxymethyl starch sodium accounts for 3/4.

The preparation method is the same as in Example 2.

Example 5

A yellow sole B dispersible tablet, the raw material composition is: 3.75% yellow sole B, 20.0% microcrystalline cellulose, 64.5% cellulose lactose, 10% cross-linked sodium hydroxymethyl starch, 1.75% micropowder silica gel. The added amount of cross-linked hydroxymethyl starch sodium accounts for 3/4.

The preparation method is the same as in Example 2.

Example 6

A yellow sole B dispersible tablet, the raw material composition is: 3.75% yellow sole B, 40.0% microcrystalline cellulose, 44.5% cellulose lactose, 10% cross-linked sodium hydroxymethyl starch, 1.75% micropowder silica gel. The added amount of cross-linked hydroxymethyl starch sodium accounts for 3/4.

The preparation method is the same as in Example 2.

Example 7

A yellow sole B dispersible tablet, the raw material composition is: 3.75% yellow sole B, 30.0% microcrystalline cellulose, 55.75% cellulose lactose, 10% cross-linked sodium hydroxymethyl starch, 0.5% micropowder silica gel. The added amount of cross-linked hydroxymethyl starch sodium accounts for 3/4.

The preparation method is the same as in Example 2.

Example 8

A yellow sole B dispersible tablet, the raw material composition is: 3.75% yellow sole B, 30.0% microcrystalline cellulose, 53.25% cellulose lactose, 10% cross-linked sodium hydroxymethyl starch, 3.0% micropowder silica gel. The added amount of cross-linked hydroxymethyl starch sodium accounts for 3/4.

The preparation method is the same as in Example 2.

Example 9

A yellow sole B dispersible tablet, the raw material composition is: 3.13% yellow sole B, 35.0% microcrystalline cellulose, 53.24% cellulose lactose, 7.5% cross-linked sodium hydroxymethyl starch, 1.13% micropowder silica gel. The added amount of cross-linked hydroxymethyl starch sodium accounts for 3/4.

The preparation method is the same as in Example 2.

Comparative example 1

Take 200g of luteolin B, make powder, pass through a 100 mesh sieve, spray an appropriate amount of ethanol with a mass fraction of 70%, add 17.5% microcrystalline cellulose, add 7.5% microcrystalline cellulose and 20% starch, pass through a 20 mesh sieve for granulation Dry, add 10% microcrystalline cellulose and 1% magnesium stearate, mix and press into tablets, the tablet weight is 0.20±0.01g.

Comparative example 2

Prescription ratio: flavin B: 3.13%, micronized silica gel: 1.13%, microcrystalline cellulose 35% and cellulose lactose 60.74%. Grind lutein B, microcrystalline cellulose, and cellulose lactose separately, pass through a 100-mesh sieve, and set aside. Weigh and mix yellow sole B, microcrystalline cellulose, and cellulose lactose according to the proportion of the prescription, use 70% ethanol to make a soft material, pass through a 20-mesh sieve to granulate, dry in an oven at 55°C~60°C to constant weight, and pass through a 20-mesh sieve Sieve, granulate, add micropowder silica gel, mix evenly, and press into tablets.

Performance test method:

1.1. In vitro dissolution test method: according to the third small cup method in the 2015 edition of "Chinese Pharmacopoeia" (Part IV) 0931 dissolution and release test method, the set temperature is 37 ° C, and the rotation speed is 75 r/min . Put the dispersible tablets into the dissolution cup, add 250mL degassed 2% sodium lauryl sulfate, take 2mL samples at the specified time, filter through a 0.45μm filter membrane, and inject into the high performance liquid chromatograph. At the same time, the same amount of fresh medium was added to the dissolution vessel, and the operation was completed within 30 s.

1.2. Testing method of hardness: use the Monsanto hardness tester method, place the pressed tablet between two pressing plates, and gradually pressurize along the diameter direction, the pressure just when it is broken is the hardness of the tablet.

1.3. Detection method of stickiness: check whether there is stickiness during tablet compression.

1.4. Detection method of disintegration time limit: Take 6 tablets from each of the prepared tablets, and test them in water at a temperature of 37°C±1°C by using a lift-type tablet disintegration apparatus.

1.5. The detection method of dispersion uniformity: take 6 pieces of Huangdusu B dispersible tablets respectively, according to the disintegration time limit inspection method (2015 edition of "Chinese Pharmacopoeia" Four General Rules 0921), the inner diameter of the stainless steel wire mesh is 710 μm, and the water temperature is 20 °C to check. Whether it passes through the sieve within 3 minutes.

1.6. Friability: The friability of 3 batches of dispersible tablets was inspected according to the tablet friability inspection method under the 0923 item of the fourth general rule of the 2015 edition of "Chinese Pharmacopoeia", and 36 tablets were taken from each batch for determination. Test for <1% weight loss, splinters and debris.

Embodiment test data sees the following table 1:

Comparative example test data sees the following table 2:

1.7. High-temperature test: Take an appropriate amount of the dispersible tablet of Huangdusu B in Example 9, put it in a suitable clean container naked, and place it at a temperature of 60°C for 10 days, take samples at 0, 5, and 10 days, and investigate the appearance, disintegration time limit, and Changes in in vitro dissolution rate and content indicators of active ingredients.

The results are shown in Table 3 below:

1.8. High humidity test

Take an appropriate amount of huangdusu B dispersible tablets in Example 9, weigh them accurately, place them naked in a suitable clean container, and place them at 25°C for 10 days at a relative humidity of 92.5% (KNO3), take samples on the 5th and 10th days, and investigate Appearance, disintegration time, in vitro dissolution rate of dispersible tablets. At the same time, accurately weigh the weight of the dispersible tablets before and after to investigate the moisture absorption and deliquescence performance of the dispersible tablets.

The experimental data is shown in Table 4 below:

1.9. Constant temperature accelerated test

Get the Huangdusu B dispersible tablets of Examples 3, 7, and 9, use aluminum-plastic bubble eye packaging, and place them for 3 months under the conditions of temperature 40°C ± 5°C and relative humidity 75% (NaCl saturated solution), respectively. Samples were taken at 0, 1, 2, and 3 months to inspect the five indicators of tablet appearance, disintegration time limit, in vitro dissolution rate, and active ingredient content, and compare each inspection indicator with the 0-month sample.

The results are shown in Table 5 below:

The test results showed that the appearance, disintegration time limit, active ingredient content and 45min in vitro dissolution rate of Huangdusu B dispersible tablets did not change significantly in the constant temperature accelerated stability test, and the tablet had good stability.

The present invention first investigates the effect of the yellow sole B dispersible tablet on the mouse sarcoma S180 solid tumor.

2.1 Test animals

Mice, weighing 18-22 g, were purchased from Shanghai Slack Experimental Animal Co., Ltd., animal certificate number: SCXK (Shanghai 2015-0005). The mice were kept at a temperature of (22±1)°C, a relative humidity of (65±10)%, and lighting time of 12 hours per day.

2.2 Test drugs

Get the luteolin B dispersible tablets prepared in Example 9 and Comparative Example 1-2, lutein B powder.

2.3 Experimental method

Using tumor-bearing mice in vivo experiments, the corresponding tumor cells were extracted from the abdomen of sarcoma S180 tumor-bearing mice, stained with trypan blue, counted, and diluted with sterile saline to (1.0-1.3)×107cells/mL in a centrifuge tube , placed on ice, and subcutaneously injected tumor cells of this concentration into the right axilla of mice, with an injection volume of 0.1 mL/mouse. Randomly divided into groups according to body weight, respectively, model group, 5-Fu group, embodiment group 1, comparative example group 1, comparative example group 2, luteolin B powder group. 24 hours after the inoculation, the drug was given by intragastric administration according to body weight. The model group was given 200 mg/kg of CMC-Na; Once; the dosage of embodiment group is the Huangdusu B dispersible tablet that 1/kg embodiment 9 prepares; The Huangdusu B dispersible tablet that comparative example group 1-2 consumption is 1/kg comparative example 1-2 prepares; Huangdusu B powder group The dosage is 6.5mg of luteolin powder and 193.5mg of CMC-Na; continuous administration for 12 days, 24 hours after the last administration, the eyeballs were picked and blood was collected for the determination of serum ALT and AST activities after centrifugation and separation of serum; tumor tissues were taken and weighed. Tumor inhibition ratio (%) = [(C-T)/C]×100, where C refers to the average tumor weight of the model group, and T refers to the average tumor weight of the drug-administered group. A significant difference in tumor weight and a tumor inhibition rate > 30% are the criteria for the drug to have anti-tumor activity.

2.4 Experimental results

Dispersible tablets are nontoxic to mice. Compared with the model group, as shown in Table 1, after the mice inoculated with sarcoma S180 were given the dispersible tablets of luteolin B continuously for 12 days, the tumor weight was significantly reduced, indicating that dispersible tablets of lutein B were effective for S180 solid tumors; Than, the embodiment group tumor weight significantly reduces, and tumor inhibition rate obviously improves, shows that yellow sole B dispersible tablet has high specific powder absorption rate, and antitumor activity is high. Compared with the comparative example group 1-2, the average tumor weight of the embodiment group was significantly reduced, and the tumor inhibition rate was significantly improved, indicating that the dispersible tablet of lutein B of the present invention has higher antitumor activity than the dispersible tablet prepared by other methods.

The present invention further investigates the inhibitory effect of the Huangdusu B dispersible tablet on human tumors.

3.1 Source of cell lines

Human liver cancer Hep3B, gastric cancer SGC-7901, and bladder cancer T24 cell lines were purchased from Shanghai Institute of Cell Biology, Chinese Academy of Sciences.

3.2 Experimental method

Cell proliferation test (MTT): cells were digested with 0.25% trypsin, centrifuged at 1000rpm, DMEM high-sugar culture medium containing 5% activated carbon inactivated serum, no phenol red, 37°C, 95% CO2 cultured for 48h (to exclude endogenous hormones Interference), that is, the cells enter the logarithmic growth phase, digest the cells with 0.25% trypsin, inoculate the cells on a 96-well culture plate at 2×103/well, each well volume is 180 μL, and the cells adhere to the wall for 24 hours. Multiple wells were set up with model photos, 5-Fu group, embodiment group, and Huangdusu B powder group respectively, and continued to observe and cultivate for 48 hours after adding the drug.

Color development and colorimetry: After 48 hours of drug-added culture, the culture plate was taken out, 20 μL of MTT solution (5 mg/mL) was added to each well, and the culture was continued for 4 hours at 37°C and 5% CO ₂ to terminate the culture. Carefully aspirate and discard the culture supernatant in the wells, add 150 μ LDMSO to each well and shake for 10 minutes to fully dissolve the crystals, select 490 nm and measure the absorbance of each well on an automatic microplate reader (BIO-TEK) (OD, proportional to the number of living cells) , to calculate the cell growth inhibition rate.

3.3 Experimental results

Cell growth inhibition rate=(OD value of control well-OD value of experimental well)/OD value of control well×100%.

Clinical Trials:

A total of 60 cases of gastric cancer were treated, aged 40-70 years, tumor diameter ≤ 3cm. After chemotherapy, the above patients were divided into 3 groups, 20 cases in each group, and they took Huangdusu B dispersible tablets, two tablets each time, twice a day, with warm water, and treated for six months.

Efficacy criteria

Healed: the symptoms disappeared; markedly effective: the symptoms basically disappeared, and the size of the tumor decreased; ineffective: the volume of the fibroids basically remained unchanged or increased by B-ultrasound.

After treatment, it was found that:

For the dispersible tablet prepared by embodiment 9, 16 cases were cured, and 4 cases were markedly effective;

For the dispersible tablet prepared in comparative example 1, 6 examples were cured, 7 examples were markedly effective, and 7 examples were invalid;

For the dispersible tablets prepared in Comparative Example 2, 4 cases were cured, 8 cases were markedly effective, and 8 cases were invalid.

It can be seen that the curative effect of the dispersible tablet prepared in Example 9 is unexpectedly higher than that of Comparative Example 1-2.

Select patients with liver cancer, gastric cancer, and bladder cancer. After chemotherapy, they will take Huangdusu B dispersible tablets, two tablets each time, twice a day, with warm water.

Case 1: Zhang XX, a 61-year-old man, was diagnosed with gastric cancer in the middle stage. During the operation, he was found to have extensive lymph node metastasis in the abdominal cavity. He took Huangdusu B dispersible tablets, two tablets each time, twice a day, with warm water, and recovered for 6 consecutive months. Follow up a case by regular visits to 1 year, no recurrence.

Case 2: Zhang XX, a 75-year-old female, was diagnosed with liver cancer in 12 years. She took Huangdusu B Dispersible Tablets, two tablets each time, twice a day, with warm water. She recovered and was followed up for 1 year without recurrence.

Case 3: Xu XX, a 68-year-old female, was diagnosed with bladder cancer. She took Huangdusu B dispersible tablets, two tablets each time, twice a day, and took it with warm water. She recovered for 6 consecutive months, and the tumor tissue disappeared. There was no recurrence after 1 year of follow-up. .

Claims (7)

1. a kind of diosbulbin B dispersible tablet, it is characterised in that it is made of following weight percent content, diosbulbin B 2.5-5.0%, Disintegrant is crosslinked Sodium Hydroxymethyl Stalcs 5-15%, and wetting agent superfine silica gel powder 0.5-3.0%, microcrystalline cellulose 20-40%, surplus is fibre The plain lactose of dimension.

2. diosbulbin B dispersible tablet according to claim 1, which is characterized in that dispersible tablet adds in dispersion tablet quality 4-6%'s Ethanol solution, the mass fraction of ethanol solution is 70%.

3. the diosbulbin B dispersible tablet according to one of claim 1-2, it is characterised in that it is made of following weight percent, Diosbulbin B 3.13% is crosslinked Sodium Hydroxymethyl Stalcs 7.5%, superfine silica gel powder 1.13%, microcrystalline cellulose 35%, cellulose milk sugar 53.24%。

4. diosbulbin B dispersible tablet according to claim 1, which is characterized in that in the crosslinking Sodium Hydroxymethyl Stalcs use Outer addition adds in, and the ratio of interior plus quality and outer dosage is 3:1.

5. diosbulbin B dispersible tablet according to claim 1, which is characterized in that dispersible tablet hardness is 40-60N.

6. a kind of preparation method of diosbulbin B dispersible tablet as described in claim 1, it is characterised in that using wet granulation process, Include the following steps：

（1）Diosbulbin B, microcrystalline cellulose, cellulose milk sugar, crosslinking Sodium Hydroxymethyl Stalcs, superfine silica gel powder are weighed by weight proportion It is finely ground respectively, it sieves with 100 mesh sieve, it is spare；

（2）By step（1）Middle diosbulbin B, microcrystalline cellulose, cellulose milk sugar, the 1/2-3/4 for being crosslinked Sodium Hydroxymethyl Stalcs quality It is uniformly mixed using equal increments method, with 70% ethyl alcohol softwood, crosses 20 mesh sieve series grains, in dry to perseverance in 55 DEG C of -60 DEG C of baking ovens Weight crosses 20 mesh sieve whole grain；

（3）Superfine silica gel powder and remaining crosslinking Sodium Hydroxymethyl Stalcs are added, is uniformly mixed, tabletting, dispersible tablet, piece weight is made 0.2±0.01g。

7. preparation method according to claim 6, which is characterized in that step（2）Middle crosslinking Sodium Hydroxymethyl Stalcs add in matter It measures as step（1）The 3/4 of middle crosslinking Sodium Hydroxymethyl Stalcs quality.