Utidelone pharmaceutical composition and preparation method therefor

Abstract

A pharmaceutical composition comprising utidelone and a cyclodextrin compound, and a preparation method therefor.

Description

A pharmaceutical composition of ortataxel and a preparation method thereof TECHNICAL FIELD

[0001] The present application relates to a pharmaceutical composition of ortataxel, especially a pharmaceutical composition of ortataxel cyclodextrin and a preparation method thereof. BACKGROUND

[0002] Ortataxel is an epothilone derivative, which has a similar pharmacological mechanism of action as paclitaxel, i.e. exerts antitumor effects by inhibiting the depolymerization of tubulin. Its chemical name is: 4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-[1-methyl-2-(2-methyl-thiazol-4-yl)-vinyl]-hexadecahydrocyclo-13-ene-2,6-ketonolide, and its chemical structure is shown as follows:

[0003] Ortataxel has very low solubility in aqueous solution, and its saturated solubility in water is less than 1 ug / ml, which rapidly crystallizes out after contacting with aqueous solution.

[0004] Like ortataxel, most epothilone compounds are water-insoluble and are easily rapidly crystallized out in aqueous medium. Therefore, the first problem to be solved in developing an injection of epothilone compound is the water-solubility of epothilone compound, and the second problem to be solved is the stability problem, to ensure the physical and chemical stability during preparation and administration.

[0005] Cyclodextrin has a series of advantages in pharmacy, such as increasing drug stability, improving the solubility of poorly soluble drugs, masking bad odor, reducing irritation, etc. Especially, hydroxypropyl-β-cyclodextrin (HPBCD) and sulfobutyl-β-cyclodextrin (SBECD) have been well verified in safety of parenteral administration, which have better water solubility, lower nephrotoxicity, lower hemolytic and local irritation, etc. Therefore, in the industry, the preparation of pharmaceutical compositions of epothilone compounds by cyclodextrin inclusion method has been widely studied. For example, patent CN200480029613.2 discloses a prescription for preparing a lyophilized preparation of epothilone, which dissolves a mixture of 10 mg of epothilone D and 0.4 g of hydroxypropyl-β-cyclodextrin in 60% tert-butyl alcohol-water solution, and then pours it into a glass bottle for lyophilization to obtain a lyophilized preparation containing epothilone D. However, unfortunately, when the lyophilized product is reconstituted into a drug solution for intravenous injection, it still needs to be pre-dissolved in a mixed solvent containing a certain amount of surfactant (such as Tween 80) and ethanol, and then diluted with normal saline. Due to the introduction of Tween 80 and ethanol, the composition still has obvious risks of irritation, hemolysis, etc. during administration. SUMMARY

[0006] According to one aspect, the present application provides a pharmaceutical composition of oltipraz, comprising oltipraz and a cyclodextrin compound.

[0007] According to some embodiments, the pharmaceutical composition of the present application comprises or consists of oltipraz, a cyclodextrin compound and human blood albumin.

[0008] According to further embodiments, the mass ratio of oltipraz to the cyclodextrin compound in the composition is 1 :60-140, for example 1 :60-120, in particular 1 :60-100.

[0009] According to some embodiments, the cyclodextrin compound is selected from one or more of hydroxypropyl beta cyclodextrin (HPBCD) and sulfobutyl-beta-cyclodextrin sodium (SBECD), preferably sulfobutyl-beta-cyclodextrin sodium (SBECD).

[0010] According to some embodiments, the mass ratio of oltipraz to human blood albumin is 1 :1-1 :10, for example 1 :2-1 :8, in particular 1 :3-1 :5.

[0011] According to some embodiments, the pharmaceutical composition of the present application further comprises a pH adjusting agent. The pH adjusting agent is for example selected from one or more of sodium hydroxide, sodium citrate, citric acid, phosphoric acid, acetic acid, glycine or hydrochloric acid, preferably an inorganic acid or inorganic salt such as sodium hydroxide, hydrochloric acid.

[0012] According to some embodiments, the pharmaceutical composition of the present application comprises or consists of oltipraz, a cyclodextrin compound and one or both of glycine and citric acid. According to further embodiments, the mass ratio of oltipraz to the cyclodextrin compound is not more than 1 :180.

[0013] According to some embodiments, the cyclodextrin compound is selected from one or more of hydroxypropyl beta cyclodextrin (HPBCD) and sulfobutyl-beta-cyclodextrin sodium (SBECD), preferably sulfobutyl-beta-cyclodextrin sodium (SBECD).

[0014] According to some embodiments, the above pharmaceutical composition further comprises a pH adjusting agent. The pH adjusting agent is for example selected from one or more of sodium hydroxide, sodium citrate, citric acid, phosphoric acid, acetic acid, glycine or hydrochloric acid, preferably an inorganic acid or inorganic salt such as sodium hydroxide, hydrochloric acid.

[0015] According to some embodiments, the pharmaceutical composition of the present application is long-term stored in the form of a lyophilized powder or a lyophilized cake.

[0016] According to another aspect, the present application provides a method for preparing a pharmaceutical composition of oltipraz, comprising the steps of:

[0017] (1) the cyclodextrin compound is dissolved in an acidic solution, preferably an inorganic acid solution, such as a hydrochloric acid solution, with a pH of < 3.0 to obtain a cyclodextrin solution;

[0018] (2) the fine powder of Ortataxel is added to the cyclodextrin solution and stirred at high speed;

[0019] (3) after the complete dissolution of Ortataxel, the pH is adjusted to 3.0-8.0, preferably 4.0-7.5, and more preferably 5.5-7.0, using a basic solution, preferably an inorganic base solution, such as a sodium hydroxide solution;

[0020] (4) human serum albumin is added or not added, and if added, the mass ratio of Ortataxel to human serum albumin is 1:1-1:10, preferably 1:2-1:1:8, and more preferably 1:3-1:5; and optionally

[0021] (5) after sterilization filtration, freeze-drying is performed.

[0022] The pharmaceutical composition of the present application can be administered by intramuscular, subcutaneous, gastrointestinal and non-gastrointestinal routes for anti-tumor treatment.

[0023] The cyclodextrin compound of the present application is a kind of cyclic oligosaccharide compound formed by connecting D-glucopyranose units through α-1, 4-glycosidic bonds, which has a conical molecular structure, a hydrophobic inner cavity and a hydrophilic outer surface, and is suitable for use in food and pharmaceutical fields, and can be divided into α-cyclodextrin, β-cyclodextrin and γ-cyclodextrin.

[0024] The human serum albumin of the present application is not limited in origin, which includes but is not limited to human serum albumin extracted from human plasma and recombinant human serum albumin.

[0025] The following is the discovery of the present inventor in the development of the Ortataxel pharmaceutical composition of the present application.

[0026] Under normal conditions, the preparation of a cyclodextrin inclusion compound of a poorly soluble compound is usually achieved by dissolving the poorly soluble compound in an organic solvent, such as ethanol, and then performing inclusion with an aqueous cyclodextrin solution. However, this preparation scheme is not suitable for all compounds. For example, when we first dissolved Ortataxel in anhydrous ethanol and then slowly dropped it into an aqueous solution of cyclodextrin or cyclodextrin and any excipient to prepare an inclusion compound, it was found that under this preparation method, the mass ratio of Ortataxel to cyclodextrin needed to reach 1:180 to prepare a cyclodextrin inclusion compound with a stability of more than 8h at room temperature. See Example 1 for details.

[0027] Another method for preparing the cyclodextrin inclusion complex of the poorly soluble compound is to directly grind the poorly soluble compound with the cyclodextrin solution using a spherical mill. However, this method cannot meet the sterility requirements of sterile preparations, and is usually used for the preparation of preparations for gastrointestinal administration, and cannot be applied to the preparation of parenteral preparations.

[0028] A compromise method for preparing the cyclodextrin inclusion complex is to directly mix the poorly soluble compound with the cyclodextrin solution and then stir vigorously. However, the poorly soluble compound is difficult to be effectively dissolved, and thus the inclusion rate is very low, the required stirring time is particularly long, the inclusion rate reproducibility is poor, and the process requirements for drug preparation cannot be met. When we tried to prepare the etidronate cyclodextrin inclusion complex, we found that a large amount of etidronate powder was not included or dissolved after 3 hours of stirring.

[0029] The present inventors have unexpectedly found that the stability of the etidronate cyclodextrin inclusion complex is significantly enhanced when human serum albumin is added. Based on the previous knowledge and experience, combined with the unexpected discovery, the inventors successfully prepared an etidronate pharmaceutical composition with a high drug-cyclodextrin ratio, very good process and clinical compatibility stability, meeting the sterile preparation process conditions, short process time, and industrial production capacity. More specifically, it is an etidronate cyclodextrin inclusion complex that meets the requirements of clinical medication. Therefore, the problems of incomplete inclusion, high cyclodextrin content, long process time, non-compliance with sterile preparation process conditions, poor stability during the preparation of the inclusion complex and during clinical compatibility have been solved.

[0030] It should be noted that cyclodextrins generally have the problem of nephrotoxicity caused by low clearance of cyclodextrins due to renal insufficiency. Therefore, the lower the proportion of cyclodextrin in the cyclodextrin inclusion complex, the more likely it is to bring clinical advantages. The recommended clinical dose of etidronate is about 50 mg. Based on the current recommended daily dose limit of hydroxypropyl β-cyclodextrin and sulfobutyl β-cyclodextrin, the mass ratio of etidronate to cyclodextrin in the etidronate cyclodextrin inclusion complex should not exceed 1:180. In some specific embodiments of the present application, the mass ratio of etidronate to cyclodextrin is even less than 1:120. Generally speaking, the higher the proportion of cyclodextrin in the drug combination, the stronger the stability of the inclusion complex, and therefore the drug combination with a higher proportion of cyclodextrin should be considered as within the scope of the present patent, without further explanation. DETAILED DESCRIPTION

[0031] The following examples are further illustrations of the application of the present application and are not intended to limit the present application in any way. The present application is set forth in greater detail in the following examples, but the application of the present application is not limited to these examples and the preparation methods used. Moreover, those skilled in the art will appreciate that the application of the present application can be subject to variations, combinations, modifications and / or improvements without departing from the scope of the present application.

[0032] Main raw materials:

[0033] Hydroxypropyl β-cyclodextrin, sulfobutyl β-cyclodextrin sodium is from Shanghai Luofu Pharmaceutical Technology (Shanghai) Co., Ltd.

[0034] Human serum albumin: from Chengdu Rongsheng Pharmaceutical Co., Ltd.

[0035] Example 1:

[0036] This example shows that the composition containing olprecorolan, hydroxypropyl β-cyclodextrin or sulfobutyl β-cyclodextrin and any one of the pharmaceutically acceptable excipients, the process feasibility of using organic solvents to completely dissolve olprecorolan in advance, and then mixing with the aqueous solution of cyclodextrin and any one of the excipients to prepare olprecorolan inclusion complex. The test results show that under the conditions of the method and the pharmaceutical composition, olprecorolan and HPBCD or SBECD cannot prepare olprecorolan cyclodextrin inclusion complex with complete inclusion at a mass ratio of 1:120; when containing a certain amount of excipients such as glycine and citric acid, the stability is improved to a certain extent.

[0037] Preparation method of olprecorolan cyclodextrin inclusion complex: a certain amount of olprecorolan is dissolved in anhydrous ethanol to prepare an olprecorolan solution containing about 100 mg of olprecorolan per 1 ml; then the cyclodextrin and any excipient are completely dissolved in 10 ml of water to obtain a cyclodextrin solution according to the test matrix described below. Slowly add 0.2 ml of the above olprecorolan solution to the cyclodextrin solution with a syringe pump, stirring while adding.

[0038] Table 1: Preparation matrix of olprecorolan-hydroxypropyl β-cyclodextrin inclusion complex

[0039] Note: "-" means that the solution is clear, "+", "++", "+++", "++++" means that the solution is observed by naked eye, the degree of turbidity or the precipitation of olprecorolan, the more the plus sign, the higher the turbidity, the more the precipitation of olprecorolan.

[0040] Table 2: Preparation matrix of olprecorolan sulfobutyl β-cyclodextrin inclusion complex

[0041] Note: "-" means the solution is clear, "+", "++", "+++", "++++" means the turbidity degree of the solution or the precipitation degree of ulotrilon observed by naked eye, the more the plus sign, the higher the turbidity, the more the precipitation of ulotrilon.

[0042] As shown in the above table, in the cyclodextrin inclusion compound of ulotrilon, the excipients glycine, citric acid and tartaric acid have a promoting effect on the inclusion of ulotrilon. The amount of ulotrilon, glycine, citric acid and tartaric acid is fixed, and the amount of sulfobutyl β-cyclodextrin is increased. The preparation method is according to the preparation method of Example 1 described above, and the test results are shown in the table below.

[0043] Note: "-" means the solution is clear, "+", "++", "+++", "++++" means the turbidity degree of the solution or the precipitation degree of ulotrilon observed by naked eye, the more the plus sign, the higher the turbidity, the more the precipitation of ulotrilon.

[0044] Example 2:

[0045] This example shows that the process of adding ulotrilon powder into an aqueous solution of hydroxypropyl β-cyclodextrin or sulfobutyl β-cyclodextrin and any one of the pharmaceutically feasible excipients, and stirring vigorously, is feasible for preparing ulotrilon inclusion compound. The test results show that under this method and pharmaceutical composition, the mass ratio of ulotrilon to cyclodextrin is 1:140, and in the presence of the excipient citric acid, the inclusion rate of ulotrilon is higher and the stability is higher, but there is a problem of too low solution pH, and after pH adjustment, the stability is poor.

[0046] Preparation method of ulotrilon cyclodextrin inclusion compound: take 10 mg of ulotrilon powder and place it in a Schlenk bottle, then add 10 ml of an aqueous solution composed of the cyclodextrin and any excipient described in the test matrix below, and stir vigorously. The test results are shown in the table below.

[0047] Note: "-" means the solution is clear, "+", "++", "+++", "++++" means the turbidity degree of the solution or the precipitation degree of ulotrilon observed by naked eye, the more the plus sign, the higher the turbidity, the more the precipitation of ulotrilon.

[0048] The pH of the sample solution of prescription 66 in the above table is about 2.7, which is too low and not suitable for intravenous infusion administration. Adjust the pH to 5.0 with sodium hydroxide solution, and during the pH adjustment process, part of the ulotrilon can be observed by naked eye. After filtering the sample solution of prescription 66 and the sample solution of prescription 75 with a 0.22 μm needle filter, place them at 25°C to observe the stability of the solution, and the results are shown in the table below.

[0049] Note: "-" means the solution is clear, "+", "++", "+++", "++++" means the degree of turbidity of the solution or the precipitation of uterine observed by the naked eye, the more the plus sign, the higher the turbidity, the more uterine precipitates.

[0050] Example 3:

[0051] Take 10 mg of uterine powder and the amount of sulfobutyl beta cyclodextrin described in the test matrix below and place them in different test tubes, add 10 ml of 0.01 mol / L hydrochloric acid solution, stir vigorously, and after 30 minutes, get a clear liquid, uterine is completely dissolved or complexed, then adjust the pH to 6.5 with sodium hydroxide solution, add 30 mg of human albumin, mix well, filter with a 0.22 μm needle filter, and place it at 25°C to investigate the stability of the solution, the test results are shown in the table below;

[0052] Note: "-" means the solution is clear, "+", "++", "+++", "++++" means the degree of turbidity of the solution or the precipitation of uterine observed by the naked eye, the more the plus sign, the higher the turbidity, the more uterine precipitates.

[0053] Example 4:

[0054] Take 10 mg of uterine powder and the amount of sulfobutyl beta cyclodextrin described in the test matrix below and place them in different test tubes, add 10 ml of 0.01 mol / L hydrochloric acid solution or 0.01 mol / L citric acid solution, stir vigorously, and after about 30 minutes, get a clear liquid, uterine is completely dissolved or complexed, then adjust the pH to 6.5 with sodium hydroxide solution, filter with a 0.22 μm needle filter, and place it at 25°C to investigate the stability of the solution, the test results are shown in the table below;

[0055] Note: "-" means the solution is clear, "+", "++", "+++", "++++" means the degree of turbidity of the solution or the precipitation of uterine observed by the naked eye, the more the plus sign, the higher the turbidity, the more uterine precipitates.

[0056] According to the experimental results, the stability of inorganic acid is significantly better than that of organic acid.

[0057] Example 5:

[0058] Take 10 mg of oxatomide powder and the amount of hydroxypropyl β-cyclodextrin described in the test matrix below into different vials, add 10 ml of 0.1 mol / L hydrochloric acid solution, stir vigorously, and after 30 minutes, a clear liquid is obtained, and oxatomide is completely dissolved or complexed. Then adjust the pH to 6.0 with sodium hydroxide solution, add 60 mg of human serum albumin, mix well, filter with a 0.22 μm needle filter, and place at 25°C to investigate the stability of the solution. The test results are shown in the table below.

[0059] Note: "-" indicates that the solution is clear, "+", "++", "+++", "++++" indicates the degree of turbidity of the solution or the precipitation of oxatomide observed by the naked eye. The more the plus signs, the higher the turbidity, and the more oxatomide precipitates.

[0060] Example 6:

[0061] Take 10 mg of oxatomide powder and the amount of hydroxypropyl β-cyclodextrin described in the table below into a vial, add 5 ml of 0.01 mol / L hydrochloric acid solution, stir vigorously, and after about 30 minutes, a clear liquid is obtained, and oxatomide is completely dissolved or complexed. Then adjust the pH to 5.0 with sodium hydroxide solution, add 40 mg of human serum albumin, mix well, filter with a 0.22 μm needle filter, and place at 25°C to investigate the stability of the solution. The test results are shown in the table below.

[0062] Note: "-" indicates that the solution is clear, "+", "++", "+++", "++++" indicates the degree of turbidity of the solution or the precipitation of oxatomide observed by the naked eye. The more the plus signs, the higher the turbidity, and the more oxatomide precipitates.

[0063] Example 7:

[0064] Take 1000 mg of oxatomide powder into a conical flask, add 50 ml of cyclodextrin solution (take 65 g of sulfobutyl β-cyclodextrin into a beaker, add 0.01 mol / L hydrochloric acid solution to completely dissolve), stir vigorously, and after about 30 minutes, oxatomide is completely dissolved. Adjust the pH of the solution to 6.8 with sodium hydroxide solution, add 3 g of human serum albumin, mix well, filter, and then divide into vials. Place in a freeze dryer and freeze dry. The typical conditions for freeze drying are pre-freezing at -40°C for about 4 h, drying at -15°C for about 24 h, and finally drying at 40°C for about 8 h to obtain the freeze-dried powder of the oxatomide cyclodextrin complex.

[0065] Example 8:

[0066] Take 3 bottles of the freeze-dried powder of Ultorfelone prepared in Example 7, dilute with normal saline to a concentration of about 0.5 mg / ml of Ultorfelone, filter with a 0.22 μm filter under a clean bench, and store at 25°C. At 4, 8, and 12 hours, respectively, check the solutions for insoluble particles according to the method for checking insoluble particles in the Chinese Pharmacopoeia 0903, and the results are shown in the following table.

[0067] Determination of the inclusion rate of Ultorfelone

[0068] Take about 2 ml of the Ultorfelone cyclodextrin inclusion solution of the freeze-dried powder of Example 7, dilute with acetonitrile to the calibration mark, mix well, and determine the amount of Ultorfelone in the solution according to the method for liquid chromatography in the Chinese Pharmacopoeia, calculate the inclusion rate of Ultorfelone, which is equal to the ratio of the amount of Ultorfelone in the cyclodextrin inclusion solution to the amount of the feed. The high performance liquid chromatography conditions are as follows:

[0069] Instrument: Waters

[0070] Chromatographic column: Agilent EORBAX Eclipse plus C18, 4.6*150mm, 5μm

[0071] Column temperature: 30°C;

[0072] Flow rate: 1.0 ml / min;

[0073] Mobile phase: water-acetonitrile (40:60);

[0074] Detection wavelength: 250 nm.

[0075] The inclusion rate of Ultorfelone in the examples is shown in the following table:

[0076] Example 10:

[0077] Take 10 mg of Ultorfelone powder and place it in a Schlenk bottle, add 5 ml of cyclodextrin solution (take 650 mg of sulfobutyl β-cyclodextrin and place it in a beaker, add 0.01 mol / L hydrochloric acid solution to completely dissolve it), and stir vigorously. After about 30 minutes, the Ultorfelone is completely dissolved, adjust the pH of the solution to 7.5 with sodium hydroxide solution, add 100 mg of human serum albumin, mix well, filter, and store at 25°C. No Ultorfelone precipitates within 12 hours.

Claims

1. A pharmaceutical composition of Utidolon, characterized in that The pharmaceutical composition comprises eutidelon and a cyclodextrin compound.

2. The pharmaceutical composition according to claim 1, characterized in that The pharmaceutical composition further comprises human serum albumin.

3. The pharmaceutical composition according to claim 1 or 2, characterized in that The mass ratio of euterol to the cyclodextrin compound in the pharmaceutical composition is 1:60-140, preferably 1:60-120, and more preferably 1:60-100.

4. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that The mass ratio of euterone to human serum albumin in the pharmaceutical composition is 1:1 to 1:10, preferably 1:2 to 1:1:8, and more preferably 1:3 to 1:

5.

5. The pharmaceutical composition according to claim 1, characterized in that The pharmaceutical composition further comprises one or more of glycine and citric acid.

6. The pharmaceutical composition according to claim 5, characterized in that The mass ratio of eutilide to the cyclodextrin compound in the pharmaceutical composition is no more than 1:

180.

7. The pharmaceutical composition according to any one of claims 1 to 6, characterized in that The cyclodextrin compound is selected from hydroxypropyl β-cyclodextrin (HPBCD), sulfobutyl-β-cyclodextrin sodium (SBECD) or a combination thereof.

8. The pharmaceutical composition according to any one of claims 1 to 7, characterized in that The pharmaceutical composition further comprises a pH adjuster, preferably an inorganic acid or an inorganic salt.

9. The pharmaceutical composition according to any one of claims 1 to 8, characterized in that The pharmaceutical composition is in lyophilized form.

10. A method for preparing the eutideron pharmaceutical composition according to any one of claims 1 to 7, characterized in that: The method comprises the following steps: 1) dissolving cyclodextrin in an acidic solution with a pH value of ≤ 3.0 to obtain a cyclodextrin solution; 2) adding euterol to the cyclodextrin solution and stirring at high speed; 3) After the euterol is dissolved, the pH is adjusted to 3.0 to 8.0 with an alkaline solution, preferably 4.0 to 7.5, and more preferably 5.0 to 7.0; 4) With or without adding human albumin, if human albumin is added, the mass ratio of euterone to human albumin is 1:1 to 1:10, preferably 1:2 to 1:8, and more preferably 1:3 to 1:5.

Images