阅读说明：本技术 一种西达本胺药物组合物及其制备方法和应用 (Sidapamide pharmaceutical composition and preparation method and application thereof ) 是由 鲁先平 王世刚 山松 赵传通 张钰 邓兴玉 潘德思 于 2020-08-27 设计创作，主要内容包括：本发明涉及药物技术领域,公开了一种西达本胺药物组合物及其制备方法和应用。本发明所述药物组合物包括西达本胺和作为载体的药用肠溶辅料。本发明提供了含有西达本胺和药用肠溶辅料的药物组合物,组合物中西达本胺作为客体分子,药用肠溶辅料为载体分子,本发明通过动物口服药代试验证明了西达本胺和药用肠溶辅料组合物的生物利用度有大幅提高,同时降低药物在胃肠道造成的不良反应,在保持疗效的情况下,可降低服用剂量,较市售西达本胺片具有更重要的临床意义。(The invention relates to the technical field of medicines, and discloses a xidapamide medicinal composition, and a preparation method and application thereof. The pharmaceutical composition comprises the cidentamine and medicinal enteric auxiliary materials used as carriers. The invention provides a pharmaceutical composition containing xidalbenamine and medicinal enteric auxiliary materials, wherein the xidalbenamine in the composition is taken as an object molecule, and the medicinal enteric auxiliary materials are taken as carrier molecules.)

1. The medicinal composition of the xidalbenamine is characterized by comprising the xidalbenamine and medicinal enteric auxiliary materials used as carriers.

2. The pharmaceutical composition according to claim 1, wherein the pharmaceutical enteric adjuvant is one or more selected from hydroxypropyl methyl cellulose acetate succinate, cellulose acetate phthalate, polyvinyl alcohol phthalate, cellulose acetate trimellitate, hydroxypropyl methyl cellulose phthalate, and acrylic resin.

3. The pharmaceutical composition according to claim 1, wherein the mass ratio of the xidalbenamine to the medicinal enteric adjuvant is 1: 1-1: 100.

4. Use of a pharmaceutical composition according to any one of claims 1 to 3 for the preparation of a preparation of xidapamide and/or a medicament for the treatment of a disease associated with the mechanism of action of histone deacetylase.

5. The use according to claim 4, wherein the diseases associated with the action mechanism of histone deacetylase comprise cancer, viral diseases, autoimmune diseases and blood system diseases.

6. A formulation of cidentamine comprising the pharmaceutical composition of any one of claims 1-3.

7. The preparation of claim 6, wherein the preparation is in the form of tablets, capsules, pills, oral liquid, granules, powders, ointments or dripping pills.

8. The preparation method of the pharmaceutical composition as claimed in claim 1, wherein the pharmaceutical composition is prepared from the cidentamine and the medicinal enteric adjuvant by a solvent evaporation method or a hot-melt extrusion method.

9. The preparation method according to claim 8, wherein the solvent in the solvent evaporation method is selected from pharmaceutically acceptable alcohols, acetone, tetrahydrofuran or any number of mixed solvents thereof.

10. The method according to claim 9, wherein the alcohol is one or more of methanol, ethanol, isopropanol, butanol, tert-butanol, and propanol.

Technical Field

The invention relates to the technical field of medicines, and particularly relates to a xidapamide medicinal composition, and a preparation method and application thereof.

Background

The xida benamine is a new molecular entity drug discovered exclusively by Shenzhen micro-core biotechnology, Inc., has novel mechanism, is a first global subtype selective Histone Deacetylase (HDAC) inhibitor and a first global oral drug for treating peripheral T cell lymphoma, and belongs to epigenetic regulators.

In the field of antitumor therapy, although the application of various novel targeted antitumor drugs improves the effective rate of tumor therapy and prolongs the progression-free life cycle (PFS) time, the drug resistance generation, metastasis and recurrence of tumors are still difficult obstacles to surmount. In most tumors, the long-term survival of the patients is not particularly significantly improved, and over 90% of tumor patients eventually die from tumor metastasis and recurrence, mainly due to immune escape of the tumor, heterogeneity of the tumor, stem cell-like and tumor resistance. In recent decades, a great deal of scientific research finds that epigenetic inheritance plays an important role in overcoming tumor immune escape, inducing differentiation of tumor stem cells related to tumor recurrence, reversing phenotypic transformation of epithelial mesenchymal cells closely related to tumor metastasis, and eliminating molecular effects such as drug-resistant cells in heterogeneous tumors. Therefore, epigenetic drugs (epirudgs) are an important hotspot in the current field of drug development.

The xidapamide belongs to an epigenetic regulator medicament, has a re-regulation effect on epigenetic abnormality related to tumorigenesis development, and acts on an epigenetic related target, namely histone deacetylase (I type 1, 2 and 3 subtypes and IIb type 10 subtypes). Histone Deacetylases (HDACs) are a class of proteases that play an important role in the structural modification and regulation of gene expression of chromosomes, and sidapipramine, as an HDAC inhibitor, acts by inhibiting the biological activity of HDACs and thus produces alterations in gene expression (i.e., epigenetic alterations) of multiple signaling pathways directed against tumorigenesis.

The solubility of the xidalbenamine in water is extremely low, the bioavailability is low, and the disadvantages of poor medicament absorption, high dosage, high digestive tract toxicity and the like in clinic are brought. Therefore, the method has important significance in improving the bioavailability of the cydariamine so as to reduce the dosage of the medicine, reduce the production cost of the medicine and reduce the toxicity of the digestive tract.

CN201310364845.4 discloses a sidaxanide solid dispersion preparation, which contains active ingredients and polyvinylpyrrolidone (PVP), the mass ratio of the two is: polyvinylpyrrolidone ═ 1: 0.5-10, and the preferable ratio is 1: 1-7, wherein the active ingredient is sidananiline or N- (2-amino-4-fluorophenyl) -4- [ N-3- (3-pyridine) acryloyl ] aminomethyl ] benzamide (hereinafter referred to as 4-fluorosidananiline). It further discloses a solid dispersion preparation, which contains the solid dispersion and one or more auxiliary materials of diluent, disintegrant, adhesive and lubricant. The active ingredient is present in an amount of 0.1-30 wt%, preferably 0.3-20 wt%, and more preferably 0.5-10 wt% based on the total weight of the solid dispersion. The advantages are that the medicine is taken orally, and the medicine is convenient to use. The solubility, stability and bioavailability of the cydarifamide are not researched and improved.

CN201410016221.8 discloses a xidalbenamine solid dispersion, a preparation method and an application thereof, wherein the weight ratio of the xidalbenamine to a water-soluble carrier material is 1: 1-1: 20, the preferable dosage form is a solid dispersion tablet prepared from the xidalbenamine and povidone K30 according to the weight ratio of 1:5, and the xidalbenamine in the solid dispersion can be highly dispersed in the water-soluble carrier material in a molecular form or an amorphous state, so that the water solubility of the xidalbenamine is greatly improved, and the dissolution rate and the bioavailability of the xidalbenamine are improved. The solubility of the xidalamine solid dispersion in water is detected, and the result shows that the solubility of the xidalamine raw material drug in water is 4.64 mu g/mL, while the solubility of the solid dispersion prepared from the xidalamine and the povidone K30 in a weight ratio of 1:5 in water is 66.7 mu g/mL, which is 14.4 times higher than that of the raw material drug. The Sidapamide solid dispersion can increase the solubility of the medicine and accelerate the dissolution rate of the medicine. The problem of dissolution of the cydapamide is solved, but the problem of bioavailability of the cydapamide is not concerned. The formulation is adopted by the commercial Sidapamide solid dispersion tablet.

CN201610855106.9 discloses a solid dispersion of E-configuration benzamide compound, wherein the compound of formula (I) can be highly dispersed in copovidone in a molecular form or an amorphous state by combining the cidentamine and the copovidone (especially in a weight ratio of 1: 2-1: 10), so that the water solubility of the compound of formula (I) is greatly improved, the dissolution rate and the bioavailability of the compound of formula (I) are improved, and the stability of the formed solid dispersion is greatly improved. The compounds of formula (I) in the solid dispersions of the invention do not degrade significantly even after standing for 10 days at elevated temperature (60 ℃), high humidity (90%) and intense light irradiation (4500 Lx). It solves the stability problem of the solid dispersion of the cydarifamide, but the bioavailability problem of the cydarifamide is not concerned.

In addition, the invention discovers that after the xidapamide and the copovidone or the povidone K30 are formed into the solid dispersion, the phenomena of nausea and vomiting can be caused under the stimulation of the xidapamide, and meanwhile, the bioavailability is low. Therefore, the preparation of the xidapamide preparation with higher bioavailability is of great significance.

Disclosure of Invention

In view of the above, the invention aims to provide a medicinal composition of xidalbenamine and a preparation method thereof, which can remarkably improve the bioavailability of the xidalbenamine and can be applied to the fields of medicinal preparation, disease treatment and the like related to the xidalbenamine.

In order to achieve the above purpose, the invention provides the following technical scheme:

a medicinal composition of xidalbenamine, which comprises the xidalbenamine and medicinal enteric auxiliary materials used as carriers.

The xidalbenamine has a structure shown in a formula (1), the chemical name of the xidalbenamine is N- (2-amino-4-fluorophenyl) -4- [ N- [ (E) -3- (3-pyridine) acryloyl ] aminomethyl ] benzamide, and in the structural formula, the configuration of the 3-pyridine acryloyl is E type.

Preferably, the invention provides a medicinal enteric auxiliary material with better effect of improving bioavailability, which is selected from one or more than two of hydroxypropyl methyl cellulose acetate succinate, cellulose acetate phthalate, polyvinyl alcohol phthalate, cellulose acetate trimellitate, hydroxypropyl methyl cellulose phthalate and acrylic resin.

Preferably, the mass ratio of the xidamine to the medicinal enteric auxiliary materials is 1: 1-1: 100, more preferably 1: 1-1: 20, and most preferably 1: 1-1: 10; in a particular embodiment of the invention, the mass ratio is 1:3, 1:5, 1:8, 1:50 or 1: 100.

The invention takes the conventional medicinal auxiliary material polyvinylpyrrolidone K30 (K30 has the effect of improving bioavailability in other medicines) of the cidam preparation as a carrier to prepare the solid dispersing agent, and the result of comparison of the bioavailability of the cidam medicine composition with the solid dispersing agent as a control shows that the AUC (area under a curve during medicine) of the solid dispersing agent is only about 60 percent of the AUC of the medicine composition, the maximum concentration of the medicine is only 836.1ng/ml, and the maximum concentration of the medicine composition can reach 2059.9 ng/ml. On the other hand, compared with the commercially available solid dispersant of the Epsoximidamide, the drug concentration of the pharmaceutical composition of the invention in blood plasma at different time points is significantly higher than that of the commercially available drug.

Based on the above significant technical advantages, the invention provides the application of the pharmaceutical composition in preparing a cideramide preparation and/or a medicine for treating diseases related to the action mechanism of histone deacetylase.

Wherein, the diseases related to the action mechanism of histone deacetylase include, but are not limited to, cancers, viral diseases, autoimmune diseases and blood system diseases.

Based on the application, the invention also provides a xidabenamine preparation which comprises the xidabenamine pharmaceutical composition, and more specifically comprises the xidabenamine pharmaceutical composition and pharmaceutically acceptable auxiliary materials. The preparation formulation includes but is not limited to tablets, capsules, pills, oral liquid preparations, granules, powder, paste and dripping pills, and all the preparations can be prepared into any release forms of sustained-release preparations, controlled-release preparations and the like.

The pharmaceutically acceptable auxiliary materials can be adjusted and selected according to the preparation form required to be prepared. In the invention, the auxiliary materials can be selected from one or more than two of a filling agent, a disintegrating agent, a binding agent and a lubricating agent. The amount of filler may be from 0% to 90%, preferably from 5% to 20%; the amount of disintegrant may be from 0% to 10%, preferably from 3% to 8%; the amount of binder may be from 0% to 20%, preferably from 0% to 5%; the amount of the pH regulator may be 0% to 20%, preferably 0% to 5%; the amount of lubricant may be 0% to 5%, preferably 0.2% to 1%.

Wherein the filler is selected from one or more of lactose, corn starch, hydroxypropyl methylcellulose, hydroxypropyl cellulose, cetyl alcohol, stearyl alcohol, ethyl cellulose, pregelatinized starch, sucrose, microcrystalline cellulose, mannitol, calcium hydrogen phosphate, calcium phosphate, xanthan gum and colloidal silicon dioxide;

the disintegrating agent is selected from one or more of starch, microcrystalline cellulose, croscarmellose sodium, carboxymethylcellulose sodium, sodium carboxymethyl starch, crospolyvinylpyrrolidone and low-substituted hydroxypropyl cellulose;

the adhesive is one or more than two of water, ethanol, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, polyvinylpyrrolidone and copovidone;

the lubricant is one or more than two of stearic acid, magnesium stearate, sodium stearyl fumarate, polyethylene glycol 4000-8000, micro-powder silica gel and talcum powder.

In addition, the invention also provides a preparation method of the pharmaceutical composition, which is prepared by a solvent volatilization method or a hot-melt extrusion method of the cidentamine and the medicinal enteric auxiliary material.

Preferably, the pharmaceutical composition is prepared by a solvent evaporation method, wherein the solvent is selected from pharmaceutically acceptable alcohols, acetone, tetrahydrofuran or any number of mixed solvents thereof.

Preferably, the alcohol is one or more of methanol, ethanol, isopropanol, butanol, tert-butanol, and propanol.

In a specific embodiment of the invention, the preparation method specifically comprises the following steps: dissolving the cidentamine and the medicinal enteric-coated auxiliary materials in a solvent, and carrying out rotary evaporation or spray drying on the obtained solution to obtain the finished product.

According to the technical scheme, the pharmaceutical composition containing the cidentamine and the specific medicinal enteric auxiliary materials is provided, the cidentamine in the composition is used as an object molecule, the medicinal enteric auxiliary materials are used as carrier molecules, and animal oral pharmaceutical surrogate tests prove that the bioavailability of the cidentamine and medicinal enteric auxiliary material composition is greatly improved, meanwhile, the adverse reaction of the medicine in the gastrointestinal tract is reduced, the taking dosage is reduced under the condition of keeping the curative effect, and the pharmaceutical composition has more important clinical significance compared with the commercially available cidentamine tablets.

Drawings

FIG. 1 shows the results of a rodenticide experiment of a pharmaceutical composition of xidabenamine;

FIG. 2 is a graph showing the mean plasma concentration versus time for dogs in the commercially available Cedaramine tablet, example 4, example 6, and example 8.

Detailed Description

The invention discloses a Sida benamine pharmaceutical composition, a preparation method and application thereof, and can be realized by appropriately improving process parameters by referring to the content. It is expressly intended that all such similar substitutes and modifications which would be obvious to one skilled in the art are deemed to be included in the invention. While the pharmaceutical compositions and methods of preparation and use of the invention have been described in terms of preferred embodiments, it will be apparent to those skilled in the art that variations and modifications, or appropriate alterations and combinations, of the pharmaceutical compositions and methods of preparation and use of the invention described herein may be made to practice and use the techniques of the invention without departing from the spirit, scope and spirit of the invention.

The present invention provides a pharmaceutical composition of xidabenamine, and a preparation method and application thereof.

Example 1: comparative solid dispersion formulations of xidabenamine

Preparing a Sidapamine solid dispersion by taking polyvinylpyrrolidone K30 as a carrier, wherein the weight ratio of Sidapamine: the polyvinylpyrrolidone K30 ratio was 1:5, and the preparation method of the Sida benamine solid dispersion was as follows:

prescription:

sidapamide 2g

Polyvinylpyrrolidone K3010 g

Proper amount of ethanol

The preparation method comprises the following steps:

(1) accurately weighing the cydariamine and the polyvinylpyrrolidone K30, carrying out water bath at 90 ℃, and dissolving in a proper amount of ethanol to form a transparent solution;

(2) carrying out rotary evaporation on the solution formed in the step (1) at 90 ℃, and drying to form a solid dispersion;

(3) and (3) taking out the solid dispersion obtained in the step (2) and crushing to prepare the xidapamine solid dispersion powder.

Example 2: the invention relates to a pharmaceutical composition of xidabenamine

The method comprises the following steps of preparing a xidamine pharmaceutical composition by taking hydroxypropyl methyl cellulose acetate succinate as a carrier, wherein the weight ratio of the xidamine: the hydroxypropyl methylcellulose acetate succinate is 1:3, and the preparation method of the xidapipramine pharmaceutical composition comprises the following steps:

prescription:

sidapamide 2g

Hydroxypropyl methylcellulose acetate succinate 6g

Proper amount of ethanol

The preparation method comprises the following steps:

(1) accurately weighing the cidamide and the hydroxypropyl methyl cellulose acetate succinate, carrying out water bath at 90 ℃, and dissolving in a proper amount of ethanol to form a transparent solution;

(2) carrying out rotary evaporation on the solution formed in the step (1) at 90 ℃, and drying;

(3) and (3) taking out the solid dispersion obtained in the step (2), and crushing to prepare the xidapine pharmaceutical composition powder.

Example 3: pharmacokinetic testing of rats

Healthy rats were selected and randomly divided into 2 groups of 6 rats (3 females and 3 males) each, a group of sidalamine solid dispersion and a group of sidalamine-hydroxypropylmethylcellulose acetate succinate (1: 3). During the test period, rats were fasted overnight before administration, blood was collected from the eye socket before administration, and plasma was isolated as a blood concentration sample of 0 h. The gastric lavage fluid is dispersed by purified water, the concentration of the gastric lavage fluid is 2mg/ml, and each rat is respectively irrigated with the dose of the cydapamide of 20 mg/kg. After administration, blood samples were collected at 15min, 0.5h,1h,2h,4h, 6h, 8h, about 0.5ml of each sample was collected, heparin sodium was anticoagulated, and after collection, the blood plasma was placed on ice and centrifuged within 1 hour and stored at-80 ℃ for testing. Drug concentrations in plasma were measured by LC-MS/MS. The results are shown in Table 1 and FIG. 1.

TABLE 1 rat drug data comparison table

Parameters (ng/ml)	Example 1	Example 2
			AUC(0-t)	2271.4	3716.4
Cmax	836.1	2059.9

As can be seen from the test results in table 1 and fig. 1, compared with the solid dispersion tablet of xidalamine, the medicinal composition of xidalamine containing hydroxypropylmethylcellulose acetate succinate can significantly improve the bioavailability of xidalamine.

Example 4: tablet containing the Sidapamide pharmaceutical composition

The method comprises the following steps of preparing a xidapamine pharmaceutical composition by taking hydroxypropyl methylcellulose phthalate as a carrier, wherein the weight ratio of the xidapamine: the hydroxypropyl methylcellulose phthalate ratio is 1:5, and the preparation method of the Sidamine tablet comprises the following steps:

prescription

The preparation method comprises the following steps:

(1) accurately weighing the Xidabenamine and the hydroxypropyl methylcellulose phthalate, dissolving the Xidabenamine and the hydroxypropyl methylcellulose phthalate in ethanol to form a transparent solution;

(2) spray drying the solution obtained in the step (1) to obtain a Xidamine-hydroxypropyl methyl cellulose phthalate composition;

(3) uniformly mixing the composition obtained in the step (2) with mannitol, microcrystalline cellulose, sodium carboxymethyl starch and polyvinylpyrrolidone, and adding water for wet granulation to obtain a soft material;

(4) drying the soft material obtained in the step (3) to prepare dry particles;

(5) adding magnesium stearate into the dried granules obtained in the step (4), and totally mixing;

(6) and (5) tabletting the total mixed material obtained in the step (5) to obtain tablets.

Example 5: granules containing the Sida benamine pharmaceutical composition

Preparing a medicinal composition of the xidapamine by using polyvinyl alcohol phthalate as a carrier, wherein the weight ratio of the xidapamine: the ratio of polyvinyl alcohol phthalate is 1:50, and the preparation method of the cilastamide granules comprises the following steps:

prescription

The preparation method comprises the following steps:

(1) accurately weighing the Xidabenamine and the polyvinyl alcohol phthalate, dissolving the Xidabenamine and the polyvinyl alcohol phthalate in tetrahydrofuran/ethanol (1: 1) to form a solution;

(2) spray drying the solution obtained in the step (1) to obtain a Xidabenamine-polyvinyl alcohol phthalate composition;

(3) uniformly mixing the composition obtained in the step (2) with lactose, hydroxypropyl cellulose and low-substituted hydroxypropyl methyl cellulose, adding water to prepare a soft material, and swinging granules to prepare granules;

(4) drying the particles obtained in the step (3) to obtain dried particles;

(5) adding silicon dioxide into the dry particles obtained in the step (4), and uniformly mixing;

(6) and (5) bagging the mixed material obtained in the step (5) to prepare granules.

Example 6: capsule containing the Sida benamine pharmaceutical composition

Preparing a medicinal composition of the cidentamine by taking acrylic resin L100-55 as a carrier, wherein the weight ratio of the cidentamine: the proportion of the acrylic resin L100-55 is 1:3, and the Sida benamine capsule and the preparation method are as follows:

prescription

The preparation method comprises the following steps:

(1) accurately weighing the Xidabenamine and the acrylic resin L100-55, dissolving the Xidabenamine and the acrylic resin in acetone to form a transparent solution;

(2) carrying out vacuum rotary evaporation on the solution obtained in the step (1) to obtain a Sida benamine-acrylic resin L100-55 composition;

(3) uniformly mixing the composition obtained in the step (2) with mannitol, microcrystalline cellulose, croscarmellose sodium and hydroxypropyl methylcellulose, adding water to prepare a soft material, and shaking the granules to prepare granules;

(4) drying the particles obtained in the step (3) to obtain dried particles;

(5) adding magnesium stearate into the dried granules obtained in the step (4), and totally mixing;

(6) and (5) filling the total mixed material obtained in the step (5) into capsules to prepare capsules.

Example 7: dry suspension containing the xidabenamine pharmaceutical composition

Preparing a pharmaceutical composition of the xidapamide by taking cellulose acetate phthalate as a carrier, wherein the weight ratio of the xidapamide: the ratio of the cellulose acetate phthalate is 1:100, and the dry suspension of the cilastamide and the preparation method are as follows:

prescription

The preparation method comprises the following steps:

(1) accurately weighing the Xidabenamine and the cellulose acetate phthalate, dissolving the Xidabenamine and the cellulose acetate phthalate in ethanol to form a transparent solution;

(2) spray drying the solution obtained in the step (1) to prepare a Xidabenamine-cellulose acetate phthalate composition;

(3) under the condition of stirring, adding sodium carboxymethylcellulose into the purified water, and continuously stirring until the sodium carboxymethylcellulose is completely dissolved;

(4) uniformly mixing the composition obtained in the step (2) with mannitol, adding the sodium carboxymethylcellulose solution obtained in the step (3), and performing wet granulation;

(5) drying the particles obtained in the step (4) to obtain dried particles;

(6) adding xanthan gum and silicon dioxide into the dried particles obtained in the step (5), and mixing and finishing the particles;

(7) and (4) subpackaging the dry suspension powder obtained in the step (6).

Example 8: capsule containing the Sida benamine pharmaceutical composition

The method comprises the following steps of preparing a xidamine pharmaceutical composition by taking hydroxypropyl methyl cellulose acetate succinate as a carrier, wherein the weight ratio of the xidamine: the hydroxypropyl methylcellulose acetate succinate is 1:8, and the Sida benamine capsule and the preparation method are as follows:

prescription

The preparation method comprises the following steps:

(1) accurately weighing the cidamide and the hydroxypropyl methyl cellulose acetate succinate, dissolving the cidamide and the hydroxypropyl methyl cellulose acetate succinate in ethanol to form a transparent solution;

(2) carrying out fluidized bed medicine feeding on the microcrystalline cellulose blank pellet core by using the solution obtained in the step (1) to prepare a Sida benamine-containing pellet;

(3) filling the pellets obtained in the step (2) into capsules to prepare capsules.

Example 9: tablet containing the Sidapamide pharmaceutical composition

Preparing a pharmaceutical composition of xidapamide with cellulose acetate trimellitate as a carrier, wherein the weight ratio of xidapamide: the proportion of cellulose acetate trimellitate is 1:10, and the preparation method of the Sidapamide tablet comprises the following steps:

prescription

The preparation method comprises the following steps:

(1) accurately weighing the Xidabenamine and the cellulose acetate trimellitate, and uniformly mixing;

(2) carrying out hot-melting extrusion on the mixture obtained in the step (1) to obtain a Sida benamine-hydroxypropyl methyl cellulose phthalate composition;

(3) uniformly mixing the composition obtained in the step (2) with calcium hydrophosphate, corn starch, crospovidone and hydroxyethyl cellulose, adding water, and performing wet granulation to obtain a soft material;

(4) drying the soft material obtained in the step (3) to prepare dry particles;

(5) adding sodium stearyl fumarate into the dried particles obtained in the step (4), and totally mixing;

(6) tabletting the total mixed material obtained in the step (5) to obtain tablets;

(7) adding Youteqi L100-55, triethyl citrate and pulvis Talci into appropriate amount of ethanol, stirring, and making into enteric coating solution;

(8) and (4) preparing the enteric coating solution prepared in the step (7), and coating the tablets prepared in the step (6) to prepare the xidapamine enteric coated tablets.

Example 10: pharmacokinetic studies in beagle dogs

12 healthy beagle dogs were selected and randomly divided into four groups of three, namely a commercially available ciladamine tablet group, an example 1 ciladamine tablet group, an example 3 ciladamine capsule group and an example 5 ciladamine capsule group. During the test period, beagle dogs were fasted overnight before administration, and venous blood was collected before administration, and plasma was separated as a blood concentration sample of 0 h. Each dog was individually drenched with 20mg (4, 5 mg/capsule) of cidam. After administration, blood samples were collected at 15min, 0.5h,1h,2h,4h,8h, approximately 0.5ml of each sample was collected, heparin sodium was anticoagulated, the samples were placed on ice after collection, and plasma was centrifuged within 1 hour and drug concentration in plasma was measured by LC-MS/MS. The results are shown in FIG. 2 and FIG. 2.

TABLE 2 LC-MS/MS determination of drug concentration (ng/ml) in plasma for various groups of dogs at various time points

As can be seen from the test results in table 2 and fig. 2, compared with the commercially available solid dispersion tablet of xidalamine (registered trademark epothilones), the bioavailability of xidalamine in vivo is effectively improved after the combination of the xidalamine and the pharmaceutical excipients of the present invention.

The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.