WO2021018318A1 - Pharmaceutical composition containing chidamide and surfactant - Google Patents

Abstract

A pharmaceutical composition containing Chidamide and a surfactant. The surfactant may be selected from sodium dodecyl sulfate, sodium laurylsulfonate, sodium n-octadecyl sulfate, lecithin, dihexyl sodium sulfosuccinate, and dioctyl sodium sulfosuccinate. Use of the surfactant greatly improves the water solubility of Chidamide, and markedly improves the bioavailability thereof.

Description

Pharmaceutical composition containing chidamide and surfactant Technical field

The present invention relates to the field of medical technology, in particular to a pharmaceutical composition containing chidamide and a surfactant and its application.

Background technique

Chidamide has a structure of the following formula (1), and its chemical name is N-(2-amino-4-fluorophenyl)-4-[N-[(E)-3-(3-pyridine)acryloyl] Aminomethyl]benzamide. In its structural formula, the configuration of 3-pyridineacryloyl is E type.

Chidamide is a new molecular entity drug discovered exclusively by Shenzhen Chips Biotechnology Co., Ltd., with a novel mechanism. It is the world's first subtype selective histone deacetylase (HDAC) inhibitor and the world's first approved treatment Oral drugs for peripheral T-cell lymphoma belong to the class of epigenetic regulators.

In the field of anti-tumor therapy, although the application of various new targeted anti-tumor drugs has improved the effective rate of tumor treatment and prolonged the progression-free survival (PFS) time, the development, metastasis and recurrence of tumor resistance are still difficult. Overcoming obstacles. In most tumors, the long-term survival rate of patients has not been significantly improved. More than 90% of tumor patients eventually die from tumor metastasis and recurrence. This is mainly due to tumor immune escape, tumor heterogeneity, and stem cell-like And tumor resistance. In the past decade, a large number of scientific studies have found that epigenetics is overcoming tumor immune escape, inducing the differentiation of tumor stem cells related to tumor recurrence, reversing the phenotypic transformation of epithelial mesenchymal cells closely related to tumor metastasis, and eliminating heterogeneity Molecular functions such as drug-resistant cells in tumors play a very important role. Therefore, epigenetic drugs (Epidrugs) have become an important hot spot in the field of drug development.

Chidamide is an epigenetic regulator drug, which can re-regulate the epigenetic abnormalities related to the occurrence and development of tumors. It acts on the epigenetic-related target-histone deacetylase (Class I, 1, 2, 3 subtypes and 10 subtypes of class IIb). Histone deacetylase (HDAC) is a type of protease that plays an important role in the structural modification of chromosomes and the regulation of gene expression. Chidamide acts as an HDAC inhibitor and acts by inhibiting the biological activity of HDAC. Changes in gene expression of multiple signaling pathways for tumorigenesis (ie, epigenetic changes).

However, the solubility of Chidamide in water is extremely small, which seriously affects its bioavailability. Therefore, there is still an urgent need to improve the bioavailability of Chidamide in the prior art.

CN201310364845.4 discloses a solid dispersion formulation of Cedaraniline, containing active ingredients and polyvinylpyrrolidone (PVP), which claims to have improved bioavailability, but there is no evidence that the formulation has satisfactory bioavailability .

CN201410016221.8 discloses a solid dispersion of chidamide, wherein the weight ratio of chidamide to water-soluble carrier material is 1:1 to 1:20, and particularly discloses chidamide and povidone K30. A solid dispersion made with a weight ratio of 1:5. In fact, this formula is used in the commercial cedarbenamide solid dispersion tablets.

CN201610855106.9 discloses a stable solid dispersion of chidamide, which comprises chidamide and copovidone.

In the prior art, there is still a need to further improve the bioavailability of chidamide. Therefore, there is still an urgent need to provide a chidamide pharmaceutical composition with improved bioavailability.

Summary of the invention

In view of this, the purpose of the present invention is to provide a chidamide pharmaceutical composition with significantly improved bioavailability in view of the shortcomings of the prior art.

The inventors unexpectedly discovered that by adding a surfactant, the bioavailability of chidamide can be significantly improved.

Therefore, in the first aspect, the present invention provides a pharmaceutical composition containing chidamide and a surfactant. Preferably, the mass ratio of chidamide and the surfactant used in the pharmaceutical composition is 1:0.1 to 1:10, more preferably 1:0.5 to 1:5.

In the pharmaceutical composition of the present invention, the surfactant is preferably selected from anionic surfactants and zwitterionic surfactants.

In some preferred embodiments, the anionic surfactant is selected from higher fatty acid salts, sulfates and sulfonates, more preferably selected from sulfates and sulfonates, further preferably selected from sodium lauryl sulfate, Sodium lauryl sulfonate, magnesium stearate, sodium dihexyl succinate and sodium dioctyl succinate; the zwitterionic surfactant is selected from lecithin, amino acid type zwitterionic surfactant and The betaine type zwitterionic surfactant is more preferably lecithin.

The present invention also provides a preparation method of the chidamide pharmaceutical composition, which includes the step of uniformly mixing chidamide and a surfactant. Optionally, the uniformly mixed chidamide and surfactant can be crushed and sieved, and then mixed with optional fillers, and after dry granulation, the obtained particles are mixed with disintegrants and binders to obtain The mixture can be tableted to obtain tablets; wherein the mass ratio of the chidamide to the surfactant used is 1:0.1 to 1:10. The surfactant may be selected from anionic surfactants and/or zwitterionic surfactants.

Anionic Surfactant

The anionic surfactant of the present invention refers to an anion which acts as a surface activity after ionization in water. As specific examples of the anionic surfactant of the present invention, for example, fatty acid salts, sulfates, sulfonates, phosphoric acid ester salts, amino acid salts, phenates, enol salts, ketosulfonamide salts, and the like can be cited. This art is well known in the art as anionic surfactants salts of higher fatty acid-based soaps, formula _{^{(RCOO -) n M n +}} , where R is typically a fatty acid hydrocarbon chain of between C ₁₁ ~ C _17, stearic acid , Oleic acid, lauric acid, etc. are more common. Examples of the anionic surfactant is a sulfated oil and advanced sulfated fatty alcohol sulfates having the general formula ^{_{R · O · SO 3 - M}} +, the range in which the aliphatic hydrocarbon chains R C ₁₂ ~ C _18. Sulfonates as anionic surfactants refer to aliphatic sulfonates, alkylaryl sulfonates, etc., and the general formulas are R·SO ₃ ^- M ⁺ and RC ₆ H ₅ ·SO ₃ ^- M ^{+, respectively} . Among them, the anionic surfactant is preferably selected from higher fatty acid salts, sulfates and sulfonates, more preferably, the anionic surfactant is selected from sulfates and sulfonates; particularly preferably, it is selected from twelve Sodium alkyl sulfate, sodium lauryl sulfonate, magnesium stearate, sodium dihexyl succinate sulfonate and sodium dioctyl succinate sulfonate.

Zwitterionic surfactant

The zwitterionic surfactant of the present invention means that the molecular structure has both positive and negative charge groups, thus having two ionic properties at the same time. As specific examples of the zwitterionic surfactant of the present invention, for example, an amino acid type, a betaine type, an imidazoline type, and an amine oxide type can be mentioned. Among them, the zwitterionic surfactant is preferably selected from lecithin, amino acid-type zwitterionic surfactant and betaine-type zwitterionic surfactant, and lecithin is more preferable. Lecithin is called soybean phospholipid or egg phospholipid depending on the source.

Particularly preferably, in the pharmaceutical composition of the present invention, the surfactant is selected from sodium lauryl sulfate, sodium lauryl sulfonate, sodium stearyl sulfate, lecithin, dihexyl succinic acid sulfonate Sodium and sodium dioctyl succinate sulfonate. Especially preferably, in the pharmaceutical composition of the present invention, the surfactant is selected from sodium lauryl sulfate, sodium lauryl sulfonate, sodium stearyl sulfate, lecithin and dioctyl succinic acid Sodium sulfonate.

In the pharmaceutical composition of the present invention, the mass ratio of chidamide and the surfactant used is 1:0.1 to 1:10, more preferably 1:0.5 to 1:5.

The pharmaceutical composition of the present invention may be in the form of a pharmaceutical preparation, especially an oral preparation. In some preferred aspects, the pharmaceutical composition of the present invention is in the form of a pharmaceutical preparation selected from the group consisting of tablets, capsules, soft capsules, pills, oral liquid preparations, granules, powders, ointments, and dropping pills. The pharmaceutical preparations are preferably tablets and capsules, preferably sustained-release preparations or controlled-release preparations.

In some embodiments, the pharmaceutical composition of the present invention may contain fillers, disintegrants, binders and/or lubricants, wherein the fillers are selected from lactose, microcrystalline cellulose and mannitol; The solution agent is selected from crospovidone, croscarmellose sodium and sodium carboxymethyl starch; the binder is selected from sodium carboxymethyl cellulose, hydroxypropyl cellulose, ethyl cellulose and poly Vinylpyrrolidone; the lubricant is selected from stearic acid, magnesium stearate, sodium stearyl fumarate, polyethylene glycol, micronized silica gel and talc.

The pharmaceutical composition of the present invention can also contain other auxiliary materials, and can be prepared into an oral preparation by a conventional method.

Preferably, the filler is selected from lactose, corn starch, hydroxypropyl methylcellulose, hydroxypropyl cellulose, cetyl alcohol, stearyl alcohol, ethyl cellulose, pregelatinized starch, sucrose, microcrystalline fiber Vegetarian, mannitol, calcium hydrogen phosphate, calcium phosphate, xanthan gum and colloidal silicon dioxide.

Preferably, the disintegrant is selected from starch, microcrystalline cellulose, croscarmellose sodium, carboxymethyl cellulose, sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone and low-substituted hydroxypropyl Cellulose.

Preferably, the binder is selected from water, ethanol, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, polyvinylpyrrolidone and copovidone.

Preferably, the lubricant is selected from stearic acid, magnesium stearate, sodium stearyl fumarate, polyethylene glycol 4000-8000, micronized silica gel and talc.

The present invention also provides the application of the pharmaceutical composition in the preparation of a medicine for the treatment of diseases related to the action mechanism of histone deacetylase, wherein the disease related to the action mechanism of histone deacetylase is preferably selected Since cancer, viral diseases, autoimmune diseases and blood system diseases.

In another aspect, the present invention also provides a method for improving the bioavailability of chidamide, including the step of mixing chidamide with a surfactant. Preferably, the surfactant is selected from anionic surfactants and zwitterionic surfactants. More preferably, the surfactant is selected from sodium lauryl sulfate, sodium lauryl sulfonate, sodium stearyl sulfate, lecithin, sodium dihexyl succinate sulfonate and dioctyl succinate sulfonate Sodium. Particularly preferably, the surfactant is selected from sodium lauryl sulfate, sodium lauryl sulfonate, sodium stearyl sulfate, lecithin and sodium dioctyl succinate sulfonate.

It should be noted that in this article, when several elements, elements or members are listed after the term "selected from", it means that it can include one of these elements, elements or members, or any combination of these elements, elements or members.

The beneficial effects of the present invention

The chidamide pharmaceutical composition of the present invention comprises chidamide and a surfactant. The chidamide pharmaceutical composition of the present invention greatly improves the water solubility of chidamide, and has higher bioavailability than commercially available chidamide preparations.

Description of the drawings

Figure 1 shows the results of rat pharmacokinetic experiments of chidamide pharmaceutical composition.

Figure 2 shows the results of the pharmacokinetic experiment of chidamine drug preparations for Beagle dogs.

Detailed ways

The invention discloses a chidamide pharmaceutical composition and a preparation method thereof, and those skilled in the art can learn from the content of this article and appropriately improve the process parameters to achieve it. In particular, it should be pointed out that all similar substitutions and modifications are obvious to those skilled in the art, and they are all deemed to be included in the present invention. The applications and pharmaceutical compositions of the present invention have been described through preferred embodiments, and relevant personnel can obviously modify or appropriately modify the applications and pharmaceutical compositions described herein without departing from the content, spirit and scope of the present invention In combination with, to realize and apply the technology of the present invention.

The following is a further description of a pharmaceutical composition and preparation method provided by the present invention.

Comparative Example 1: Preparation of Chidamide solid dispersion

prescription:

The preparation method is as follows:

(1) Accurately weigh cedarbenamide and polyvinylpyrrolidone K 30, dissolved in a proper amount of ethanol in a water bath at 90°C to form a transparent solution;

(2) Rotate and dry the solution formed in step (1) at 90°C to form a solid dispersion;

(3) The solid dispersion obtained in step (2) is taken out and pulverized to prepare a solid dispersion powder of chidamide.

Preparation Example 2: Preparation of Chidamide-Sodium Lauryl Sulfate (1:1.5) Composition

prescription:

Cida amine 2g 40.00%

Sodium lauryl sulfate 3g 60.00%

The preparation method is as follows:

(1) Accurately weigh Chidamide and Sodium Lauryl Sulfate in the sealed bag;

(2) Mix the composition of step (1) for 20 minutes and mix uniformly to form a composition of Chidamide-sodium lauryl sulfate.

Preparation Example 3: Preparation of Chidamide-Sodium Dodecyl Sulfonate (1:3) Composition

prescription:

Cida amine 2g 25.00%

Sodium dodecyl sulfonate 6g 75.00%

The preparation method is as follows:

(1) Accurately weigh Chidamide and Sodium Dodecyl Sulfonate in the sealed bag;

(2) Mix the composition of step (1) for 20 minutes and mix uniformly to form a chidamide-sodium dodecyl sulfonate composition.

Biological Activity Example 4: Rat pharmacokinetic study of chidamide pharmaceutical composition

Eighteen healthy rats were selected and randomly divided into 3 groups, each with 6 (3 females and 3 males), which were the chidamide solid dispersion group (comparative example 1) and chidamide-12 Sodium alkyl sulfate (1:1.5) composition group (Preparation Example 2), Chidamide-sodium dodecyl sulfonate (1:3) composition group (Preparation Example 3). During the test, the rats were fasted overnight before administration, and blood was taken from the orbit before administration, and the plasma was separated, which was used as the 0h blood concentration sample. The gastric fluid was dispersed in purified water, and the concentration of the gastric fluid was 2mg/ml. Each rat was given a dose of 20 mg/kg of Chidamide. After administration, blood samples were collected at 15min, 0.5h, 1h, 2h, 4h, 6h, 8h, and each sample was collected about 0.5ml, heparin sodium was anticoagulated, placed on ice after collection, and centrifuged within 1 hour The plasma should be stored at -80°C for testing. The drug concentration in plasma was measured by LC-MS/MS. The test results are shown in Table 1 and Figure 1.

Table 1 Rat pharmacokinetic data comparison table

Parameters (ng/ml)	Comparative Example 1	Preparation Example 2	Preparation Example 3
AUC(0-t)	2714.0	5300.6	5267.2
Cmax	785.0	2610.9	2151.0

According to the test results in Table 1 and Figure 1, it can be seen that compared with Cedarene amine solid dispersion tablets, the Cedarene amine agent composition containing sodium lauryl sulfate or sodium dodecyl sulfonate can significantly improve Bioavailability of Chidamide.

In order to further verify that the pharmaceutical composition containing the surfactant and the chidamide agent can indeed improve the bioavailability of chidamide, the pharmacokinetic study of the shaped preparation in beagle dogs was also carried out.

Preparation Example 5: Preparation of Chidamide-Sodium Lauryl Sulfate Pharmaceutical Composition (1:0.5)

Prescription (1000 tablets):

The preparation method is as follows:

(1) Accurately weigh sodium lauryl sulfate and chidamide, add an appropriate amount of water, and stir to obtain a suspension;

(2) Weigh microcrystalline cellulose, lactose, sodium carboxymethyl cellulose, and hydroxypropyl methyl cellulose and mix them evenly;

(3) adding the suspension of step (1) to the mixture of step (2), wet granulation and drying, and granulation;

(4) Tablets can be obtained by pressing the obtained dry granules.

Preparation Example 6: Preparation of Chidamide-Sodium Stearyl Sulfate Pharmaceutical Composition (1:1)

Prescription (1000 tablets)

The preparation method is as follows:

(1) Mix octadecyl sodium sulfate and chidamide, and sieving;

(2) Mixed with microcrystalline cellulose and mannitol, dry granulation;

(3) Mix the obtained granules with sodium carboxymethyl starch and polyvinylpyrrolidone;

(4) Tablets can be obtained by compressing the obtained mixture.

Preparation Example 7: Preparation of Chidamide-Sodium Dodecyl Sulfonate Pharmaceutical Composition (1:3)

Prescription (1000 tablets):

The preparation method is as follows:

(1) Accurately weigh the sodium dodecyl sulfonate and chidamide, add an appropriate amount of water, and stir to obtain a suspension;

(2) Weigh microcrystalline cellulose, mannitol, sodium carboxymethyl starch, and polyvinylpyrrolidone, feed them into a fluidized bed, and perform fluidized bed granulation and drying;

(3) Sizing the particles obtained in the fluidized bed;

(4) The obtained granules can be compressed into tablets.

Comparative Example 8: Preparation of Chidamide-Poloxamer 188 pharmaceutical composition (1:5)

Prescription (1000 tablets):

The preparation method is as follows:

(1) Mix Poloxamer 188 and Chidamide evenly, crush and sieve;

(2) Mix the above mixture with pregelatinized starch, mannitol, hydroxypropyl cellulose, and cross-linked polyvinylpyrrolidone uniformly, add water for wet granulation to obtain a soft material;

(3) Dry the above-mentioned soft materials and granulate them;

(4) The obtained granules can be compressed into tablets.

Preparation Example 9: Preparation of Chidamide-Lecithin Pharmaceutical Composition (1:5)

prescription

The preparation method is as follows:

(1) Accurately weigh lecithin and chidamide, add an appropriate amount of water, and stir to obtain a suspension;

(2) Weigh corn starch, calcium phosphate, low-substituted hydroxypropyl cellulose, and copovidone and mix them evenly;

(3) Add the step 1 suspension to the step 2 mixture, wet granulation and drying, and granulate;

(4) The obtained dried granules are bagged to obtain granules.

Preparation Example 10: Preparation of Chidamide-Sodium Dihexyl Succinate Sulfonate Composition (1:8)

Prescription (1000 tablets):

The preparation method is as follows:

(1) Mix sodium dihexyl succinate sulfonate and chidamide with appropriate amount of water;

(2) Mixed with microcrystalline cellulose and mannitol, wet granulation;

(3) Mix the obtained granules with sodium carboxymethyl starch and copovidone;

(4) Tablets can be obtained by compressing the obtained mixture.

Preparation Example 11: Preparation of Chidamide-dioctyl succinate sodium sulfonate pharmaceutical composition (1:10)

Prescription (1000 tablets)

The preparation method is as follows:

(1) Add water to microcrystalline cellulose to prepare soft material, use extrusion spheronization method to prepare blank pellet core, dry and sieving;

(2) Prepare a coating solution containing chidamide, sodium dioctyl succinate sulfonate, polyvinylpyrrolidone and water;

(3) Place the blank pellet core in a fluidized bed, coat the blank pellet core with the above coating solution to obtain the drug-loaded pellets, dry, sieving, and fill the drug-loaded pellets in the empty capsule shell, namely Get the capsule.

Biological Activity Example 12: Pharmacokinetics Study of Chidamide Pharmaceutical Composition in Beagle Dogs

Fifteen healthy beagle dogs were selected and randomly divided into 5 groups, three in each group, namely the commercially available chidamide tablet group, the example 6 group, the example 8 group, the example 9 group and the example 11 group. During the test, the Beagle dogs were fasted overnight (10-14 hours) before administration, and venous blood was collected before administration, and plasma was separated, which was used as the 0h blood concentration sample. Each dog was given 20 mg of chidamide (4 tablets, 5 mg/tablet). After administration, blood samples were collected at 15min, 0.5h, 1h, 2h, 4h, and 8h, each sample was collected about 0.5ml, heparin sodium anticoagulation, placed on ice after collection, and centrifuged within 1 hour to separate the plasma. Store at -80℃ for testing. The drug concentration in plasma was measured by LC-MS/MS. The test results are shown in Table 2 and Figure 2.

Table 2 LC-MS/MS determination of drug concentration in dog plasma of each group at different time points (ng/mL)

According to the test results in Table 2 and Figure 2, it can be seen that it is combined with the commercially available Chidamide solid dispersion tablets (registered trademark Aipusha) and Chidamide containing the nonionic surfactant poloxamer 188 Compared with substances, the chidamide pharmaceutical composition containing anionic surfactants and zwitterionic surfactants can significantly improve the bioavailability of chidamide.

Claims (10)

1. A pharmaceutical composition containing chidamide and a surfactant.
2. The pharmaceutical composition according to claim 1, wherein the surfactant is selected from anionic surfactants and zwitterionic surfactants.
3. The pharmaceutical composition according to claim 2, wherein the anionic surfactant is selected from higher fatty acid salts, sulfates and sulfonates, preferably selected from sulfates and sulfonates, more preferably selected from dodecyl Sodium sulfate, sodium lauryl sulfonate, magnesium stearate, sodium dihexyl succinate sulfonate and sodium dioctyl succinate sulfonate; the zwitterionic surfactant is selected from lecithin, amino acid type zwitterionic surface The active agent and betaine type zwitterionic surfactant are preferably lecithin.
4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the surfactant is selected from the group consisting of sodium lauryl sulfate, sodium lauryl sulfonate, sodium stearyl sulfate, lecithin, two Sodium hexyl succinate sulfonate and sodium dioctyl succinate sulfonate.
5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the surfactant is selected from sodium lauryl sulfate, sodium lauryl sulfonate, sodium stearyl sulfate, lecithin and di Sodium octyl succinate sulfonate.
6. The pharmaceutical composition according to any one of claims 1-5, wherein the mass ratio of chidamide to the surfactant used is 1:0.1 to 1:10, preferably 1:0.5 to 1:5.
7. The pharmaceutical composition according to any one of claims 1 to 6, which is in the form of a pharmaceutical preparation, especially an oral preparation.
8. The pharmaceutical composition according to any one of claims 1 to 6, which is a pharmaceutical preparation form selected from the group consisting of tablets, capsules, soft capsules, pills, oral liquid preparations, granules, powders, ointments, drops Pills, preferably tablets and capsules, or preferably sustained or controlled release formulations.
9. The pharmaceutical composition according to any one of claims 1-8, which contains fillers, disintegrants, binders and lubricants, wherein the fillers are selected from lactose, microcrystalline cellulose and mannitol; The disintegrant is selected from crospovidone, croscarmellose sodium and sodium carboxymethyl starch; the binder is selected from sodium carboxymethyl cellulose, hydroxypropyl cellulose, ethyl cellulose And polyvinylpyrrolidone; the lubricant is selected from stearic acid, magnesium stearate, sodium stearyl fumarate, polyethylene glycol 4000-8000, micronized silica gel and talc.
10. The use of the pharmaceutical composition according to any one of claims 1-9 in the preparation of a medicament for the treatment of diseases related to the action mechanism of histone deacetylase, wherein the action mechanism of the histone deacetylase is The related diseases are preferably selected from cancer, viral diseases, autoimmune diseases and blood system diseases.

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