WO2014090168A1

WO2014090168A1 - Nanoscale docetaxel and preparation method thereof

Info

Publication number: WO2014090168A1
Application number: PCT/CN2013/089174
Authority: WO
Inventors: 张旭旭; 张志安; 武超
Original assignee: 清华大学深圳研究生院
Priority date: 2012-12-13
Filing date: 2013-12-12
Publication date: 2014-06-19
Also published as: CN102973490B; CN102973490A

Abstract

Nanoscale docetaxel particles and a preparation method thereof. The nanoscale docetaxel particles use silicon dioxide aerogel as a carrier of the docetaxel. The preparation method is as follows: first dissolving the docetaxel in anhydrous ethanol, then adding the silicon dioxide aerogel, drying after full adsorption, subsequently adding purified water, feeding into an emulsifying machine for emulsification, homogenizing through a high pressure homogenizer, and drying the obtained homogenate to obtain the nanoscale docetaxel particles.

Description

Nano-scale docetaxel and preparation method thereof

Technical field

The present invention relates to an antitumor drug docetaxel, and more particularly to a nanoscale docetaxel and a process for the preparation thereof.

Background technique

Docetaxel is a taxane compound which can be obtained by semi-synthesis of a non-cytotoxic precursor compound 10-deacetyl gibberellin II extracted from Taxus chinensis. It was approved by the US FDA in 1998. Currently the most effective taxane antitumor drugs are used clinically. The action mechanism of docetaxel is similar to that of paclitaxel, but the antitumor activity is 1.3-12 times that of paclitaxel, and it has a good effect on cancers such as breast cancer, pancreatic cancer, and non-small cell lung cancer.

Due to the poor water solubility of docetaxel, the current clinical use mainly includes frozen powder injection and water injection. In order to meet the requirements of clinical injection concentration, the surfactants Tween 80 and ethanol are added to the currently marketed docetaxel injection. Practice has confirmed that the toxic side effects of this injection are serious, and these excipients added for the dissolution are the main factors causing toxic side effects.

On the other hand, since anti-tumor drugs represented by docetaxel are coping with a rapidly progressing malignant disease, unlike the use of common drugs, they need to be administered in large doses under the conditions of human body tolerability (MTD), and anti-tumor drugs. While killing tumor cells, the effect on normal cells is almost inevitable, so the serious side effects and poor safety are the general characteristics of such drugs.

How to solve the poor absorption of docetaxel, improve bioavailability, and reduce the side effects of drugs has become an international major problem that has not been overcome in the pharmaceutical field for decades.

In recent years, studies on modifying or encapsulating docetaxel in different carrier materials to prepare nanoparticles containing Tween 80 and significantly increasing the solubility of docetaxel have become hot topics. Nanoparticles, also known as nanoparticles (including nanospheres and nanoquinones), are nanoscale colloidal drug delivery systems. Drug-loaded nanosystems should meet the following criteria: Can be aggregated and maintained at designated sites, with appropriate release rates, properties Stable and easy to use. The ideal nanoparticle should have a higher drug loading and encapsulation efficiency, suitable preparation conditions and purification methods. The carrier can be biodegradable, low toxicity or non-toxic, and has appropriate particle shape and particle size, and long Body cycle time.

At present, there are many research reports on paclitaxel nanoparticles, but they have not solved the problem fundamentally. The oral bioavailability of docetaxel is low. After oral administration, a large part of the nanoparticles are not absorbed and directly excreted. Only a small part of the nanoparticles are absorbed. If the absorption of the drug is at a low level, then the absorbed dose is 100. The fractional error will be significant. For a given dose, if the uptake of the microparticles exceeds the expected value, then toxicity will occur; and if the amount of absorption is less or the concentration of the drug is below the therapeutic dose range, the treatment will result in treatment. failure.

Summary of the invention

In view of the low solubility of docetaxel, the low oral bioavailability, and the toxic side effects of existing docetaxel injections, a first object of the present invention is to provide a novel nano-sized polyene paclitaxel granule.

In order to achieve the above object, the present invention provides a nano-sized docetaxel granule characterized by: a silica aerogel as a carrier of docetaxel, a porosity of the silica aerogel

95 to 99%, a pore diameter of 10 to 50 nm, a specific surface area of 200 to 1000 m ² /g, a density of 3 to 300 kg/m ³ , a colloidal particle diameter of 1 to 50 nm, and the docetaxel is adsorbed at the site. The form in the pores of the silica aerogel forms docetaxel particles having a diameter of less than 100 nm.

Further, the mass ratio of the docetaxel to the silica aerogel is 1:0.5-20. A pharmaceutically acceptable oral preparation can be prepared from the above-described nano-sized docetaxel granules.

Further, the oral preparation is a tablet, a pill, a powder, a capsule, a granule or a suspension. A pharmaceutically acceptable injection or suppository can be prepared from the above nano-sized docetaxel granules.

Another object of the present invention is to provide a process for the preparation of the above-described nano-sized docetaxel granules, characterized in that the method comprises the steps of:

(1) dissolving docetaxel in absolute ethanol;

(2) adding a silica aerogel to the above ethanol solution;

(3) drying after docetaxel and silica aerogel are completely absorbed;

(4) adding purified water to the dried product, and feeding it to an emulsifier for emulsification;

(5) feeding the emulsion obtained in the step (4) to a high-pressure homogenizer for homogenization;

(6) After the homogenized liquid obtained in the step (5) is dried, nano-sized docetaxel particles are obtained.

When the silica aerogel described in the step (2) is hydrophobic, it is subjected to heat treatment at 300 to 1000 ° C before the addition of the ethanol solution to cause the alkyl group on the surface to disappear and be hydrophilic.

Further, the ratio of the mass of the docetaxel to the volume of the anhydrous ethanol is 1:5 to 200. Further, the drying in the step (3) is natural drying, oven drying or freeze drying.

Further, the amount of purified water added in the step (4) is 20 to 200 ml/g of docetaxel.

Further, the drying in the step (6) is spray drying.

Beneficial effects:

1. The present invention successfully prepared nano-scale docetaxel for the first time using silica aerogel as a carrier. Unlike the existing nano-sized docetaxel, the nano-sized docetaxel has a diameter below 100 nm, reaching material science. The nanoscale of the category is the true nanoscale docetaxel. Although particles smaller than Ιμιη are called nanoparticles, it is preferred to develop particles with a particle size of less than 100 nm because these particles exhibit some unique physical properties and thus exhibit potentially different and useful biological properties. . For example, due to the microcirculation of the capillaries of the body and the limitation of the cell barrier, the optimal particle size of the drug particles that can enter the blood circulation and be absorbed by the body is 10-100 nm. Therefore, the nano-sized docetaxel of the present invention has a qualitative leap in bioavailability.

2. The drug loading of the nano-sized docetaxel granules of the invention can reach more than 90%, which is unmatched by the existing liposome nanoparticles and polymer nanoparticles, and the drug loading amount can be matched with the nanocrystalline drug. Suspensions are comparable, but the production method is more simple and cheaper.

3. In the nano-scale docetaxel particles of the invention, docetaxel is loaded into numerous nano-scale cavities of silica aerogel to form an independent "nano-dispersion" which does not agglomerate, and the structure is extremely stable, directly It has solved the international problem of preparation of micro-nano drug research because agglomeration cannot be made into medicine, and difficult-to-dissolve drugs are difficult to improve bioavailability. The nano-sized docetaxel is an efficient, low-toxic, economical, "targeting function" anti-tumor drug, which solves the problem of dissolution and absorption of docetaxel by a new physical mechanism of "nanodispersion", The full effect of the drug and the unprecedented increase in oral bioavailability have realized the targeted aggregation from systemic toxicity to the tumor site in the treatment of docetaxel antitumor drugs, and solved many problems that have been solved internationally and domestically for decades. The bioavailability of docetaxel injection is low, the toxic side effects are large, the curative effect is poor, and the treatment cost is high. In the nano-level docetaxel drug, this low toxicity characteristic comes from two aspects: First, the use of the harmful solvent Tween 80 in the injection dosage form is avoided, so that the bioavailability of the drug is increased and the toxicity is greatly reduced; The targeting effect of the systemic action of the docetaxel drug on the tumor site reduces systemic toxicity.

4. Oral anti-tumor drugs have long been regarded as the most advanced technology in the pharmaceutical field, and they have been incapable for decades. The nano-level docetaxel provided by the invention realizes a brand new mouth with nano-uptake as the main absorption mode The mechanism of action, and the new structure of "nano-solid dispersion", the solubility of docetaxel is greatly increased, and it can be absorbed orally. It breaks through the international exclusion zone where docetaxel can not be absorbed orally. For the first time, oral replacement injection is directly realized at the material level. bioavailability. Because the oral dosage form does not require the use of cosolvent Tween

80, reduced toxic side effects, and expanded the applicable population. The emergence of a docetaxel oral dosage form in place of an injectable dosage form has enabled the family chemotherapy that has been expected for many years to be truly realized, bringing revolutionary advances in anti-tumor therapeutic drugs. Moreover, under the premise that the original clinical drug and the original indication are unchanged or broader, the injection is changed to the oral administration, and the compliance of the patient is greatly improved, and it is easy to be clinically accepted. The oral dosage form overcomes the complicated manufacturing process of the injection type, high equipment and packaging requirements, and high production cost defects.

5. The precursor of the silica aerogel used as a carrier in the nano-level docetaxel of the present invention is inexpensive, readily available, and has been widely used in medicines and foods, and has been used for many years by national and international standards. The silicone-based edible edible material, which is also one of the excipients described in the Handbook of Pharmaceutical Excipients, is therefore reliable in the safety of the nano-sized docetaxel of the present invention.

The antitumor effect of the nano-sized docetaxel of the present invention is demonstrated below by an anti-tumor mouse experiment _: the silica aerogels used in the experiments are each selected from silica aerogels having the following properties: Porosity 95 ~ 99%, pore size is 10 ~ 50nm, specific surface area is 200 ~ 1000m ² /g, density is 3 ~ 300kg / m ³ , and the colloidal particle diameter of the network is l ~ 50nm.

I. The efficacy experiment of the project team of Tsinghua University Shenzhen Graduate School

1. Materials: Balb/c rats, female, weighing (18±2) g, purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.; experimental use of Taxotere, UK AVENTIS Pharma Dagenham,

(Imported Drug Registration No.: H200990493); Experimental nano-polyene paclitaxel is the dry powder obtained in Example 1 of the present invention.

2. Establishment of animal model A sufficient amount of tumor cells were collected, resuspended in a centrifuge tube with PBS, and subcutaneously inoculated into the back of the rat at 2× ^{10 6} cells/0.1 ml per point.

3. Experimental grouping and dosing regimen After the tumor model was established, the tumor diameter of the mice was 4-6 mm, grouped according to 5/group. Refer to the drug dosage form usage and dosage, the latest "Clinical Oncology Manual" related literature and previous experimental results, oral bioavailability according to 20% ~ 30%, determine the dosing regimen; blank group (only one, for each group reference), Injection of docetaxel group, trade name Taxotere (UK AVENTIS Pharma Dagenham), once daily, intraperitoneal injection; docetaxel raw material group, oral gavage, once a day; nano-polyene paclitaxel group, Oral gavage, 1 time a day.

4. Detection method Animals were normally reared after administration, and the general state of the animals was observed every day, and the body weight of the animals was recorded. The tumor diameter (vernier caliper) was measured twice a week to calculate the tumor volume (V): v = ( ab ² ) /2 (where a is the long diameter of the tumor and b is the short diameter of the tumor). Compare each group of relative tumors (RTV): RTV = v _t / v ₀ , where V. The resulting tumor volume was measured for the day of the divided dose (DayO), and v _t is the tumor volume at each measurement;

The tumor inhibition rate (VIR) was calculated from the relative tumor volume:

VIR= ( 1 ^RTV treatment group) xl00%

RTV negative control group

5. Experimental results

5.1 Docetaxel treatment of human metastatic rat liver cancer BEL-7402 experimental results are shown in Table 1 and Figure 4

Table 1

Relative tumor inhibition rate%

Oral dose time 4d 7d lid 14d 17d 21d 24d 28d 31d Mondo 40mg/kg A 20.68 2.58 14.33 4.1 6.06 6.11 18.68 8.12 -4.85 Paclitaxel 80mg/kg B 37.3 34.05 70.39 64.78 64.6 73.79 71.27 69.36 71.76 Note: Docetaxel 40 mg/kg group, 1 death, 5 rats/group;

Oral nano-polymyrosine 80mg/kg group, 1 death, 5 / group.

.2 Docetaxel in the treatment of human metastatic rat non-small cell lung cancer NCI-1299 experimental results are shown in Table 2 and Table 2

Relative tumor inhibition rate%

Oral nano multi dose time 4d 7d lid 14d 17d 21d

Taxol 80mg/kg A 20.43 52 47.82 54.11 67.51 36.36 ~ Note: Menopausal nano-polyene paclitaxel 80mg/kg group, 1 death, 5 /If^

5.3 Docetaxel treatment of human transferred mouse breast cancer MCF-7 experimental results are shown in Table 3 and Figure 6

table 3

Relative tumor inhibition rate%

Oral nano multi-dose time 4d 7d lid 14d Taxol 80mg/kg A 20.38 16.98 26.45 37.68

160mg/kg B 27.68 32.43 49.89 39.71 Note: Menopausal nano-polyene paclitaxel 80mg/kg group, 1 death, 5 / group;

Oral nano-multiple; paclitaxel 160 mg/kg group, no death, 5 rats/group.

5.4 Discussion of results

1. In the experiment, the anti-tumor drugs should be used as large as possible in order to quickly kill the characteristics of cancer cells. The dosage is designed according to the maximum tolerance (MTD), and the therapeutic dose of human metastatic tumor-bearing mice is anti-tumor drugs. Preclinical studies examine the most direct method of drug safety;

2. Tumor-inhibiting experiments were carried out on tumor-bearing mice by transplanting tumor cells with three kinds of humans. According to the "Technical Guidelines for Non-Clinical Research of Cytotoxic Anticancer Drugs", the relative tumor inhibition rate is not less than 40%, and oral nano-polyene paclitaxel meets the requirements.

2. Entrusted Nanjing Kaiji Biotechnology Development Co., Ltd.

1, the purpose of the real insurance:

According to the "Guidelines for Pharmacodynamics of Antitumor Drugs" and "Technical Guidelines for Non-Clinical Research of Cytotoxic Antitumor Drugs", test whether the test samples have inhibitory effects on the growth of human lung cancer cells A549 xenograft tumors and Strength of action.

2. Samples tested:

Docetaxel injection: Zhejiang Wanma Pharmaceutical Co., Ltd., batch number: H20051044, specifications: 20mg/0.5ml. Dilute with 2 ml of the diluted solution before use, and then dilute to the desired concentration with physiological saline.

Nano-polyene paclitaxel: The dry powder obtained in the first embodiment of the present invention is now called ready-to-use. After being mixed with an analytical balance, distilled water is added, and ultrasonically dissolved into a suspension, and then administered by intragastric administration.

3. Test animals:

Source, germline, strain: BALB/c mice, provided by the Experimental Animal Center of the Chinese Academy of Military Medical Sciences.

Laboratory Animal Production License: SCXK (Jun) 2007-004

Certificate number: 0001015

Laboratory Animal Use License: SYXK (Su) 2012-010

Age: 4-5w

Weight: 18-22g

Gender: Male Number of animals: 6 in each group, a total of 30.

4, group and dosage plan are shown in Table 4

Table 4

5. Experimental method:

5.1 Model preparation

The cultured human lung cancer A549 suspension was collected at a concentration of ¹ ×10 ⁷ cells/ml, and each of 0.1 ml was inoculated subcutaneously in the right axilla of the mouse.

5.2 Grouping and administration

The diameter of the transplanted tumor was measured with a vernier caliper. After 11 days of inoculation, the animals were randomly divided into groups of 6 animals each growing to 50-75 mm ³ . At the same time, the rats in each group were started to be administered. The dosing regimen and the group were shown in the dosing regimen. The antitumor effect of the test samples was dynamically observed using the method of measuring the tumor diameter. After the end of the administration, the mice were sacrificed and the tumor pieces were surgically removed and weighed.

5.3 Observation indicators

The formula for calculating tumor volume (TV) is:

TV = l/2 ab ² where a and b represent the length and width, respectively.

Calculate the relative tumor volume (RTV) based on the measured results. The formula is:

RTV = V _t / V ₀ V. When administered in divided cages (i.e. d0) measuring the resulting tumor volume, V _t is the tumor volume at each measurement.

Evaluation index of antitumor activity: Relative tumor growth rate T/C (%), calculated as follows:

T/C (%) = X 100 T _RTV : treatment group RTV; C _RTV : model group RTV C RTV

Evaluation index of antitumor activity: Tumor growth inhibition rate (%), the calculation formula is as follows:

Model group mean tumor weight - mean tumor weight of the drug-administered group

Tumor growth inhibition rate = χ100%

Model group mean tumor weight

5.4 statistical processing

Mean values were expressed as X Shi SD, and inter-group analysis was statistically processed using the t-test. The results were statistically analyzed using SPSS (Standards for Packages).

6. Experimental results:

table 5

Effects of test samples on body weight of human lung cancer cell line A549 xenograft tumor

Table 6

Effects of test samples on the growth volume of human lung cancer cell A549 xenograft tumor

(X soil SD, n=6, unit: cm ³ )

Tumor volume RTV T/C Tumor volume RTV T/C model 3 control group 0.102+0.025 2.066+0.554 - 0.132+0.037 2.665+0.652 - commodity polyene-lOmg/kg 0.044±0.022 0.907+0.540 43.90% 0.055+0.024 1.113 Soil 0.559 41.75% Nanopolyene-50mg/kg 0.069 soil 0.025 1.348士0.360 65.26% 0.067土0.018 1.323+0.296 49.66% Nanopolyene-lOOmg/kg 0.067+0.030 1.348 soil 0.541 65.23% 0.077+0.037 1.545 soil 0.724 57.97% Nanopolyene-200mg/kg 0.063+0.025 1.181士0.481 57.14% 0.073+0.027 1.372+0.534 51.48% The sixth time seventh

Number of times

Group

Tumor volume RTV T/C Tumor volume RTV T/C model control group 0.180+0.035 3.643+0.609 - 0.232 soil 0.061 4.672士1.045 - commodity multi-women-10mg/kg 0.058+0.020 1.181士0.539 32.61% 0.063+0.019 1.262+0.395 27.02% Nanopolyene-50mg/kg 0.084±0.027 1.660+0.449 45.56% 0.108士0.051 2.125+0.958 45.49% Nanopolyene-100mg/kg 0.085+0.033 1.713+0.646 47.02% 0.109士0.027 2.179+0.436 46.64% Nano Alkene-200mg/kg 0.091+0.030 1.704±0.615 46.77% 0.113+0.040 2.130 soil 0.860 45.60%

Table 7

Inhibition of human lung cancer cell A549 xenograft tumor growth by test sample

(X Shi SD, n=6)

Commercial polyene-lOmg/kg 6 21.6+0.9 0.051+0.013 intraperitoneal injection 10mg/kg 5 3 days once 25 nanometer polyene-50mg/kg 6 20.7 soil 1.0 0.050 soil 0.008 oral administration 50mg/kg 14 daily administration 25 nanometers Polyene-lOOmg/kg 6 21.5+0.9 0.051 soil 0.011 Oral gavage 100mg kg 14 Daily administration of 25 nanometer polyene-200mg/kg 6 20.8+0.9 0.054+0.006 Oral gavage 200mg kg 14 Daily administration 25

In this experiment, a human lung cancer cell A549 xenograft tumor model was established, and the anti-tumor activity of the test sample nano-Docetaxel was evaluated using this model. The experimental results were as follows: The tumor inhibition rates of the low dose 50 mg/kg group, the medium dose 100 mg/kg group and the high dose 200 mg/kg group of the test sample were 49.75%, 69.85% and 78.89%, respectively. The tumor control rate of docetaxel in the positive control group was 78.89%. The conclusion is: Nano-Docetaxel has obvious anti-tumor effect, and there is significant difference between the middle dose group and the high dose group, P<0.01.

DRAWINGS

Figure 1 is an electron micrograph of a silica aerogel of the present invention;

Figure 2 is an electron micrograph of a docetaxel bulk drug;

Figure 3 is an electron micrograph of the nano-sized docetaxel of the present invention;

Figure 4 is a graph showing the relative tumor inhibition rate of human metastatic rat liver cancer BEL-7402 in an anti-tumor mouse experimental study;

Figure 5 is a graph showing the relative tumor inhibition rate of human metastatic rat non-small cell lung cancer NCI-1299 in an anti-tumor mouse experimental study;

Figure 6 is a graph showing the relative tumor inhibition rate of human metastatic mouse breast cancer MCF-7 in the results of an anti-tumor mouse experimental study. detailed description

The present invention will be further described in detail with reference to the accompanying drawings, which are to be construed as the invention.

The silica aerogels used in the following examples are all selected from silica aerogels having the following characteristics: porosity of 95 to 99%, pore diameter of 10 to 50 nm, and specific surface area of 200 to 1000 m ² /g. The density of the colloidal particles of the network is 3 ~ 300kg / m ³ , and the diameter of the colloidal particles is 1 ~ 50nm.

Example 1

The nanoscale docetaxel of this example was prepared as follows:

1. Docetaxel bulk drug (Shanghai Zhongxi Dimensional Drug Co., Ltd.) lg, dissolved in anhydrous ethanol 20ml;

2. Add 2 g of silica aerogel after heat treatment at 500 °C for adsorption;

3. After the adsorption is complete, dry in an oven at 60 ° C;

4, after drying, add 100ml of purified water, 25000rpm / min ordinary emulsifier emulsified, 5min;

5, high pressure homogenizer (Shanghai Donghua GYB 30-6S), 400bar, cycle 6 times, lOmin;

6. Spray the homogenized liquid in an experimental spray dryer (Shanghai Shunyi Science and Technology SP-1500). Parameters: Temperature 130 ° C, flow rate 500 ml / h, spray head: 0.75 mm, dry to obtain nano-sized docetaxel granules .

Example 2

The nanoscale docetaxel of this example was prepared as follows:

1. Docetaxel bulk drug (Shanghai Zhongxi Dimensional Drug Co., Ltd.) lg, dissolved in anhydrous ethanol 5ml;

2. Add 0.5g of silica aerogel after heat treatment at 1000 °C for adsorption;

3. After the adsorption is complete, it is naturally dry;

4, after drying, add 20ml of purified water, 25000rpm / min ordinary emulsifier emulsified, 5min;

5, high pressure homogenizer (Shanghai Donghua GYB 30-6S), 400bar, cycle 8 times, lOmin;

Example 3 The nanoscale docetaxel of this example was prepared as follows:

1, paclitaxel bulk drug (Shanghai Zhongxi Three-dimensional Drug Co., Ltd.) lg, add absolute ethanol 150ml dissolved;

2. Add 15 g of hydrophilic silica aerogel for adsorption;

3. After the adsorption is complete, freeze-dry;

4, after drying, add 150ml of purified water, 25000rpm / min ordinary emulsifier emulsified, 5min;

5, high pressure homogenizer (Shanghai Donghua GYB 30-6S), 400bar, cycle 7 times, lOmin;

Example 4

The nanoscale docetaxel of this example was prepared as follows:

1. Docetaxel bulk drug (Shanghai Zhongxi Dimensional Drug Co., Ltd.) lg, dissolved in 200 ml of absolute ethanol;

2. Adding 20 g of silica aerogel after heat treatment at 300 °C for adsorption;

3. After the adsorption is complete, dry in an oven at 60 ° C;

4, after drying, add 200ml of purified water, 25000rpm / min ordinary emulsifier emulsified, 5min;

Example 5

The nanoscale docetaxel of this example was prepared as follows:

1, paclitaxel bulk drug (Shanghai Zhongxi Three-dimensional Drug Co., Ltd.) lg, add anhydrous ethanol 70ml dissolved;

2. Add 7 g of silica aerogel after heat treatment at 700 °C for adsorption;

3. After the adsorption is complete, freeze-dry;

4. Another 6g of PEG-4000 is added to 400ml of absolute ethanol to dissolve;

5. Add the solid after lyophilization in step 3 to the above ethanol solution of PEG-4000, ultrasonic emulsifier Emulsified for 3 min;

6. The emulsion of step 5 is dried in a thermostatic oven at 60 ° C for 12 hours;

7. Grinding step 6 The dried solid is passed through a 200 mesh sieve to obtain nano-sized docetaxel granules. Example 6

The nano-sized docetaxel granules obtained in Examples 1 to 5 were uniformly mixed with an appropriate amount of microcrystalline cellulose, starch and magnesium stearate, and then tableted by a tableting machine to obtain a nano-sized docetaxel tablet of the present invention.

Example 7

The nano-sized docetaxel granules obtained in Examples 1 to 5 were directly loaded into a hard gelatin shell to obtain a nano-sized docetaxel capsule of the present invention.

Example 8

The nano-sized docetaxel granules obtained in Examples 1 to 5 were added to an aqueous solution, and the mixture was stirred to obtain a nano-sized docetaxel suspension of the present invention. The suspension may be administered orally, or may be prepared as an injection according to the preparation standard of the injection.

Example 9

The nano-sized docetaxel granules obtained in Examples 1 to 5 and an appropriate amount of Witepsol were prepared by a hot melt method to obtain a nano-sized docetaxel suppository of the present invention.

Claims

A nano-sized docetaxel granule, characterized in that: the silica aerogel is used as a carrier of docetaxel, and the porosity of the silica aerogel is 95 to 99%, and the pore diameter is 10~ 50 nm, a specific surface area of 200 to 1000 m ² /g, a density of 3 to 300 kg/m ³ , a colloidal particle diameter of 1 to 50 nm, and the docetaxel adsorbed in the pore of the silica aerogel The medium form forms docetaxel particles having a diameter of less than 100 nm.

The nano-sized docetaxel granule according to claim 1, wherein the mass ratio of the polyene paclitaxel to the silica aerogel is 1:0.5 to 20.

3. A pharmaceutically acceptable oral preparation made from the nano-sized docetaxel granules according to claim 1 or 2.

4. The oral preparation according to claim 3, wherein the oral preparation is a tablet, a pill, a powder, a capsule, a granule or a suspension.

A pharmaceutically acceptable injection or suppository made of the nano-sized docetaxel particles according to claim 1 or 2.

The method for preparing nano-sized docetaxel particles according to any one of claims 1 to 5, wherein the method comprises the steps of:

(1) dissolving docetaxel in absolute ethanol;

(2) adding a silica aerogel to the above ethanol solution;

(3) drying after docetaxel and silica aerogel are completely absorbed;

7. The method for preparing nano-sized docetaxel particles according to claim 6, wherein: when the silica aerogel described in the step (2) is hydrophobic, it is required to be added before the ethanol solution is added. Heat treatment at 300 ~ 1000 °C makes it hydrophilic.

The method for producing nano-sized docetaxel particles according to claim 6, wherein the ratio of the mass of the docetaxel to the volume of the anhydrous ethanol is 1:5 to 200.

The method for preparing nano-sized docetaxel granules according to claim 6, wherein the amount of purified water added in the step (4) is from 20 to 200 ml/g of docetaxel.

The method for producing nano-sized docetaxel particles according to claim 6, wherein the drying in the step (6) is spray drying.