CN109528664B - Lyophilized powder containing ubenimex-antitumor drug synergistic prodrug derivative and preparation method thereof - Google Patents
Lyophilized powder containing ubenimex-antitumor drug synergistic prodrug derivative and preparation method thereof Download PDFInfo
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Abstract
The invention relates to the field of pharmaceutical chemistry, and discloses a freeze-dried powder containing ubenimex-antiedemic drug synergistic prodrug derivatives and a preparation method thereof. The freeze-dried powder contains a pharmaceutical active component and an excipient, wherein the mass ratio of the pharmaceutical active component to the excipient is 1: 0.5-6, wherein the pharmaceutical active component is a prodrug derivative of ubenimex or an optical isomer, a diastereoisomer, a racemic mixture and pharmaceutically acceptable salts thereof. The freeze-dried powder containing the ubenimex-antiedemic drug synergistic prodrug derivative can prolong the retention time of the drug in vivo, improve the pharmacokinetic property of the drug and improve the bioavailability of the drug, thereby achieving better antitumor effect.
Description
Technical Field
The invention relates to the field of medicinal chemistry, in particular to lyophilized powder containing ubenimex-antitumor drug synergistic prodrug derivatives and a preparation method thereof.
Background
Ubenimex (Bestatin) is a dipeptide-structured compound found in the culture broth of Streptomyces olivaceus (Streptomyces olivoreticuli), and is marketed in 1987 as an immunopotentiator in Japan for the treatment of leukemia; ubenimex was marketed domestically in 1998. Ubenimex can inhibit APN activity (IC50 is 2.5-16.9 mu M), can block the effect of tumor stem cells, but hardly has the capacity of inhibiting the proliferation of tumor cells, so that the combined application of ubenimex and other cell antitumor drugs can greatly improve the curative effect of ubenimex. Literature research shows that the combined use of ubenimex and pentafluorouracil in a mouse liver cancer transplantation tumor experiment is obviously better than the independent and separate use of tumor inhibition activities (J Clin Invest 2010, 120, 3326-one 3339), and the research provides a good experimental basis for the combined application of ubenimex and other chemotherapeutic drugs. Clinically, ubenimex can be used in combination with chemotherapy, radiotherapy and in combination with leukemia, multiple myeloma, myelodysplastic syndrome, and other solid tumors.
5-fluorouracil (5-fluorouracil, 5FU) is a class of anti-metabolic antitumor drugs widely applied to clinic, has definite anti-tumor effect and is always used as the first choice drug for treating gastric cancer, rectal cancer, breast cancer and the like. However, the defects of serious bone marrow suppression and gastrointestinal reaction, short half-life period, poor selectivity and the like in the use of 5-fluorouracil limit the wide application of the 5-fluorouracil. In recent years, researchers have reduced or avoided 5FU deficiency by various approaches, and many prodrugs of 5FU have been synthesized and some have been used clinically, such as FTO, HCFU, CAP, 5' dFUrd, BOF-A2, ATFU, etc. In addition, N of 5FU3The urea derivative of (a) forms a prodrug 5FU by the elimination principle, which is as follows:
lenalidomide (Lenalidomide) was developed by Gelgene, usa and is a derivative of thalidomide and is used clinically for the treatment of myelodysplastic syndrome and for the treatment of multiple myeloma in combination with dexamethasone. Lenalidomide has an effect on various biological pathways within the cell. The clinical I, II stage research shows that the compound has inhibition effect on various tumors, including multiple myeloma, prostatic cancer, thyroid cancer, renal cancer, melanoma, liver cancer and chronic lymphocytic leukemia.
Epirubicin (Epirubicin) is an antibiotic antineoplastic drug and has a structure of an isomer of doxorubicin. The main anti-tumor action mechanism of epirubicin is that epirubicin can be directly inserted between DNA nucleobase pairs to interfere the transcription process, thereby preventing the formation of mRNA and inhibiting the synthesis of DNA and RNA. In addition, the study finds that epirubicin also has an inhibitory effect on topoisomerase II and is a cell cycle nonspecific drug. It is mainly used for various solid tumors such as acute leukemia, nephroblastoma, soft tissue sarcoma, bladder cancer, testicular cancer, prostatic cancer, gastric cancer, malignant lymphoma, breast cancer, bronchogenic carcinoma, ovarian cancer, liver cancer (including primary hepatocellular carcinoma and metastatic cell cancer) and the like in clinic. At present, the combined application of epirubicin is more, such as combining with paclitaxel, combining with sorafenib for advanced breast cancer and the like.
Cytarabine (Cytarabine) is a glycoside compound formed by cytosine and arabinose, is a competitive inhibitor of DNA polymerase, can inhibit the biosynthesis of DNA in vivo, and is mainly used for treating leukemia clinically. However, clinical studies have found that cytarabine has a series of disadvantages: poor lipid solubility, low bioavailability, large toxic and side effects and the like. Therefore, scientists research the related diseases of the combination treatment of the cytarabine and other medicines, thereby improving the medicinal activity and the chemical stability of the cytarabine and greatly improving the clinical curative effect of the cytarabine (the combination of the cytarabine and other medicines such as fludarabine, mitoxantrone and the like for treating various diseases such as leukemia, lymphoma and the like).
The chemical structural formulas of ubenimex (Bestatin), 5-fluorouracil (5-fluorouracil, 5FU), Lenalidomide (Le), Cytarabine (Cytarabine, Cy) and Epirubicin (Epirubicin, Ep) are shown in the specification.
At present, the mutual prodrug becomes an important strategy for designing a medicament aiming at multiple pathogenesis and multiple case links of malignant tumors. The medicine is metabolized and degraded in vivo, releases a plurality of pharmacodynamic structures and then is respectively combined with different action parts to realize the synergistic regulation effect, thereby generating better pharmacodynamic effect, reducing toxic and side effects and the like. The synergistic prodrug has single physicochemical property and uniform pharmacokinetic property compared with the combined drug, and can avoid the problems of interaction among components after the drug is mixed, asynchronous absorption, distribution and metabolism of each component and the like.
Disclosure of Invention
The invention aims to overcome the defects of the existing antitumor active compounds, and provides freeze-dried powder containing ubenimex-antitumor drug synergistic prodrug derivatives and a preparation method thereof.
The invention provides a freeze-dried powder containing ubenimex-antitumor drug synergistic prodrug derivatives, which contains a drug active component and an excipient, wherein the mass ratio of the drug active component to the excipient is 1: 0.5-6, wherein the pharmaceutical active component is a prodrug derivative of ubenimex shown in formula (I) or an optical isomer, a diastereoisomer, a racemic mixture and pharmaceutically acceptable salts thereof,
wherein R in the formula (I) is a compound residue with antitumor activity.
Preferably, R is
Preferably, the mass ratio of the pharmaceutically active component to the excipient is 1: 0.8-2.
Preferably, the excipient is at least one of mannitol, glucose and lactose.
The invention also provides a method for preparing the freeze-dried powder containing the ubenimex-antitumor drug synergistic prodrug derivative, which comprises the following steps:
(1) stirring the active pharmaceutical ingredient, the excipient and the water for injection until the active pharmaceutical ingredient, the excipient and the water for injection are completely dissolved to obtain a freeze-dried stock solution;
(2) pre-freezing the freeze-dried stock solution at-25 to-40 ℃ for 1 to 3 hours, vacuumizing to 5 to 30Pa after freezing, heating to-5 to-15 ℃ at the speed of 1 to 3 ℃ per hour, carrying out sublimation drying treatment for 10 to 20 hours, heating to 20 to 40 ℃ at the speed of 5 to 10 ℃ per hour, and carrying out resolution drying treatment for 5 to 10 hours.
Preferably, the volume ratio of the total amount of the pharmaceutically active component and the excipient to the water for injection is 5-20: 100, more preferably 8 to 15: 100.
in the invention, ubenimex (Bestatin) is fused with other compounds with antitumor activity (such as 5-fluorouracil, lenalidomide, epirubicin and cytarabine) through a urea bond by adopting a pharmacophore split principle, and a series of novel synergistic prodrugs are designed and synthesized. Under the action of in vivo enzyme, ubenimex and another anticancer drug fragment can be metabolized to release ubenimex, ubenimex exerts its stem cell inhibiting effect, and the compound with antitumor activity exerts its specific drug effect, thereby realizing the synergistic effect of the two drugs. Therefore, the freeze-dried powder containing the ubenimex-antineoplastic drug synergistic prodrug derivative can prolong the retention time of the ubenimex-antineoplastic drug in vivo, improve the pharmacokinetic property of the ubenimex-antineoplastic drug and improve the bioavailability of the ubenimex-antineoplastic drug, thereby achieving better antineoplastic effect.
Drawings
FIG. 1 is a liquid chromatogram of compound 5FU-bestatin prepared in preparation example 1;
FIG. 2 is a graph showing the stability of compound 5FU-bestatin prepared in preparation example 1 in artificial gastric juice;
FIG. 3 is a graph showing the stability of compound 5FU-bestatin prepared in preparation example 1 in artificial intestinal juice;
FIG. 4 is a graph showing the stability of compound 5FU-bestatin prepared in preparation example 1 in human plasma.
Detailed Description
The following detailed description of embodiments of the invention refers to the accompanying drawings. It should be understood that the detailed description and specific examples, while indicating the present invention, are given by way of illustration and explanation only, not limitation.
The endpoints of the ranges and any values disclosed herein are not limited to the precise range or value, and such ranges or values should be understood to encompass values close to those ranges or values. For ranges of values, between the endpoints of each of the ranges and the individual points, and between the individual points may be combined with each other to give one or more new ranges of values, and these ranges of values should be considered as specifically disclosed herein.
The freeze-dried powder containing ubenimex-antitumor drug synergistic prodrug derivatives contains active pharmaceutical ingredients and excipients.
In the freeze-dried powder, the mass ratio of the pharmaceutical active component to the excipient is 1: 0.5 to 6, preferably 1: 0.8-2.
In the invention, the active pharmaceutical ingredient is a prodrug derivative of ubenimex shown in formula (I) or optical isomer, diastereoisomer, racemic mixture and pharmaceutically acceptable salt thereof,
wherein R in the formula (I) is a compound residue with antitumor activity.
In a preferred embodiment, in formula (I), R is a 5-fluorouracil residue, a lenalidomide residue, a cytarabine residue or an epirubicin residue, each of which has the following structure:
in the above preferred embodiment, the prodrug derivative of ubenimex as a pharmaceutically active ingredient has the following structural formula:
for the compound of the pentafluorouracil-ubenimex (5FU-Bestatin), the preparation method can comprise the following steps: reacting the pentafluorouracil with triphosgene under the catalysis of activated carbon, and then reacting with ubenimex to obtain the target compound 5 FU-Bestatin.
The specific synthetic route is as follows:
reaction conditions a: BTC, activated carbon, Py,0 ℃, wherein BTC is triphosgene, Py is pyridine
The preparation method comprises the following specific steps:
adding 0.65g of pentafluorouracil (5mmol) into a reaction bottle, adding 20ml of pyridine to completely dissolve the pentafluorouracil, adding 0.65g of activated carbon, slowly adding 0.5g of triphosgene in ice bath, continuously reacting for 1 hour in ice bath, extracting the phosgene, and flushing N2And the process is carried out three times. Under ice-bath, 1.7g of ubenimex (5mmol) was slowly added, followed by reaction at room temperature for 12 hours. The activated carbon was filtered, extracted with ethyl acetate, washed 3 times with 6mol/L hydrochloric acid solution, then washed 3 times with saturated brine, and dried over anhydrous sodium sulfate. And (5) evaporating the ethyl acetate until solid is separated out, putting the ethyl acetate into a refrigerator for crystallization, and filtering to obtain a white product.
For the compound lenalidomide-ubenimex (Le-Bestatin), the preparation method can comprise the following steps: the lenalidomide reacts with triphosgene under the catalysis of activated carbon, and then reacts with ubenimex to obtain the target compound Le-Bestatin.
The synthetic route is as follows:
reaction conditions a: BTC, activated carbon, Py,0 ℃, wherein BTC is triphosgene, Py is pyridine
For the compound cytarabine-ubenimex (Cy-Bestatin), the preparation method can comprise the following steps: reacting cytarabine with triphosgene under the catalysis of activated carbon, and then reacting with ubenimex to obtain a target compound Cy-Bestatin.
The synthetic route is as follows:
reaction conditions a: BTC, activated carbon, Py,0 ℃, wherein BTC is triphosgene and Py is pyridine for the compound epirubicin-ubenimex (Ep-Bestatin), which can be prepared by: the epirubicin reacts with triphosgene under the catalysis of activated carbon and then reacts with ubenimex to obtain the target compound Ep-Bestatin.
The synthetic route is as follows:
reaction conditions a: BTC, activated carbon, Py,0 ℃, wherein BTC is triphosgene, Py is pyridine
The "pharmaceutically acceptable salts" of the present invention are those which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio.
In the present invention, the excipient may be a conventional choice in the art. In a specific embodiment, the excipient is at least one of mannitol, glucose, and lactose.
The invention also provides a method for preparing the freeze-dried powder containing the ubenimex-antitumor drug synergistic prodrug derivative, which comprises the following steps:
(1) stirring the active pharmaceutical ingredient, the excipient and the water for injection until the active pharmaceutical ingredient, the excipient and the water for injection are completely dissolved to obtain a freeze-dried stock solution;
(2) pre-freezing the freeze-dried stock solution at-25 to-40 ℃ for 1 to 3 hours, vacuumizing to 5 to 30Pa after freezing, heating to-5 to-15 ℃ at the speed of 1 to 3 ℃ per hour, carrying out sublimation drying treatment for 10 to 20 hours, heating to 20 to 40 ℃ at the speed of 5 to 10 ℃ per hour, and carrying out resolution drying treatment for 5 to 10 hours.
In the method of the present invention, the volume ratio of the total amount of the pharmaceutically active ingredient and the excipient to the water for injection may be 5 to 20: 100, preferably 8 to 15: 100.
the present invention will be described in detail below by way of examples, but the scope of the present invention is not limited thereto.
Preparation example 1
Adding 0.65g of pentafluorouracil (5mmol) into a reaction bottle, adding 20ml of pyridine to completely dissolve the pentafluorouracil, adding 0.65g of activated carbon, slowly adding 0.5g of triphosgene in ice bath, continuously reacting for 1 hour in ice bath, extracting the phosgene, and flushing N2And the process is carried out three times. Under ice-bath, 1.7g of ubenimex (5mmol) was slowly added, followed by reaction at room temperature for 12 hours. The activated carbon was filtered, extracted with ethyl acetate, washed 3 times with 6mol/L hydrochloric acid solution, then washed 3 times with saturated brine, and dried over anhydrous sodium sulfate. And (3) evaporating ethyl acetate until solid is separated out, putting the ethyl acetate into a refrigerator for crystallization, and filtering to obtain a white product which is the compound 5FU-Bestatin, a white solid and a yield: 36.7%, melting point 165-. MS-ESI: [ M-1 ]]＝463.6；[M-1+Na]485.8. The nuclear magnetic resonance hydrogen spectrum data are as follows:
300MHz 1H NMR1(d6-DMSO)δ＝0.65(d，J＝5.7Hz，3H)，0.74(d，J＝5.7Hz，2H)1.49(m,1H),2.76-2.82(m,1H),2.88-2.96(m,1H)4.01(m,1H),4.21-4.28(m,1H),4.34-4.21(m,1H),6.69-6.71(d,1H),7.20-7.34(m,5H),7.72(d,1H)，8.33(d，1H)9.44(d，1H)12.44(d，1H)12.66(s，1H)。
according to a method similar to that of preparation example 1, a compound Le-Bestatin, a compound Cy-Bestatin and a compound Ep-Bestatin can be prepared.
Test example 1
(1) In vitro enzyme inhibition
1. Materials and methods
Aminopeptidase N, substrate L-leucine-p-nitroaniline (from Sigma Co.)
Preparation of buffer, 12.89gNaH2PO4·2H2Dissolving O in a 1000ml volumetric flask, adding fresh boiled and cooled distilled water to constant volume to obtain 50mM phosphate buffer solution with pH of 7.2, and standing at room temperature for later use; dissolving aminopeptidase N in the buffer solution to prepare a solution with 0.1 IU/mL; substrate L-leucine-p-nitroaniline is dissolved in DMSO to prepare a solution of 16mmol/mL, and the solution is placed in a refrigerator for standby.
2. Experimental procedure
| Numbering | Aminopeptidase N solution (μ L) | Substrate solution (μ L) | Buffer solution (mu L) | Inhibitors |
| 100% of the |
10 | 5 | 185 | 0 |
| |
0 | 5 | 195 | 0 |
| |
10 | 5 | 145 | 40 |
mu.L of the aminopeptidase N solution, 5. mu.L of the substrate L-leucine-p-nitroaniline solution, and 40. mu.L of the compound at different gradient concentrations were added to a 96-well plate, and 200. mu.L of the mixture was supplemented with 50mM phosphate buffer solution (pH7.2), and 100% of the groups contained no inhibitor. Blank was made up to 200. mu.L with 5. mu.L substrate in buffer. Incubation was carried out at 37 ℃ for 0.5 hour and the absorbance was measured at a wavelength of 405 nm. The inhibition rate was calculated according to the following formula:
the IC50 was obtained for each compound by fitting curves based on the concentration of the compound and the corresponding inhibition using origine 7.5 software, and the results are shown in table 1 below.
TABLE 1
The results of in vitro enzyme inhibition experiments show that the target compound 5FU-Bestatin shows the inhibition effect on aminopeptidase N, and the inhibition activity is equivalent to that of the positive drug ubenimex.
(2) In vitro efficacy test (MTT method)
MTT method is used to detect the growth inhibition rate of the compound on ovarian clear cell carcinoma ES-2 cell strain, human leukemia K562 cell strain, human prostate cancer PC-3 cell strain and human colon cancer HCT-116 cell strain. Cells in exponential growth phase were taken, washed with Hank's solution, and then single cells were digested with 0.02% trypsin + 0.05% EDATA, and viable cells were counted at 95% or more by Trypan blue (Trypan blue) staining. Cells were seeded in 96-well plates at 5000 cells/well and different concentrations of compounds were added (blank for reading wells without cells and 100% for wells without cells, each set of three replicate wells, 5FU-Bestatin as compound positive control). At 37 ℃ and 5%CO2After 48h incubation, 100. mu.L of 5% MTT staining solution was added to each well, and after 4h further incubation, centrifugation was carried out at 2500rpm for 12min, and then the plate was discarded, and DMSO was added at 100. mu.L/well. The OD value of absorbance per well was measured at 570nm (absorption wavelength) and 630nm (auxiliary wavelength) on a microplate reader, and the OD value was measured as OD570-OD630The difference of (a) is calculated. The cell growth inhibition rate was calculated by the following formula (OD value in the formula is OD)570-OD630Difference of (d):
the results are shown in Table 2.
TABLE 2
In vitro pharmacodynamic experiments show that the target compound 5FU-Bestatin has certain proliferation inhibition effect on the cells. Compared with positive control drugs of ubenimex (Bestatin) and pentafluorouracil (5FU), the compound has better proliferation inhibition activity on ovarian clear cell carcinoma ES-2, human leukemia K562, human prostate cancer PC-3 and human colon cancer HCT-116 than ubenimex and pentafluorouracil.
(3) In vitro stability assay (HPLC method)
The compound 5FU-Bestatin is studied by artificial gastric juice, artificial intestinal juice and human plasma, and provides basis for further animal experiments.
The preparation of the artificial gastric juice and the artificial intestinal juice in the experiment refers to the second part of the Chinese pharmacopoeia. Chromatographic conditions are as follows: a venusil XBP C-18 column (4.6 mm. times.150 mm,5 μm); mobile phase: acetonitrile-methanol-0.2% aqueous formic acid (8-47-45, v/v/v); sample introduction amount: 20 mu L of the solution; flow rate: 1.0 mL/min; detection wavelength: 258 nm; column temperature: room temperature; the retention time t of the compound 5FU-Bestatin was 6.133min (shown in FIG. 1).
The stability results of compound 5FU-Bestatin are shown in FIGS. 2, 3 and 4: as can be seen from the figure, the compound 5FU-Bestatin is stable in artificial gastric juice and slowly degrades in artificial intestinal blood and human plasma. Thus, the compound 5FU-Bestatin is expected to be designed to slowly degrade in vivo to release the original drug.
Example 1
Accurately weighing 0.5g of compound 5FU-Bestatin and 0.5g of mannitol in a sterile environment, putting the mixture into a clean preparation container, adding 4ml of water for injection, stirring until the mixture is completely dissolved, then adding the water for injection to 5ml, and stirring uniformly to obtain a freeze-dried stock solution.
Filling the freeze-drying stock solution into a 10ml tube glass bottle, half plugging, and transferring into a freeze dryer for freezing treatment, wherein the specific freeze-drying process comprises the following steps: quickly freezing the freeze-dried stock solution to-30 ℃, lasting for 2 hours, vacuumizing to 15Pa, heating to-10 ℃ at the speed of 2 ℃ per hour, carrying out sublimation drying treatment for 15 hours, heating to 30 ℃ at the speed of 8 ℃ per hour, carrying out desorption drying treatment for 8 hours, fully plugging, and capping to obtain the freeze-dried powder A1.
Example 2
Accurately weighing 0.3g of compound Le-Bestatin and 0.6g of glucose in a sterile environment, putting the mixture into a clean preparation container, adding 4ml of water for injection, stirring the mixture until the mixture is completely dissolved, then adding the water for injection to 5ml, and stirring the mixture uniformly to obtain a freeze-dried stock solution.
Filling the freeze-drying stock solution into a 10ml tube glass bottle, half plugging, and transferring into a freeze dryer for freezing treatment, wherein the specific freeze-drying process comprises the following steps: quickly freezing the freeze-dried stock solution to-40 ℃, lasting for 1 hour, vacuumizing to 30Pa, heating to-15 ℃ at the speed of 1 ℃ per hour, carrying out sublimation drying treatment for 10 hours, heating to 20 ℃ at the speed of 5 ℃ per hour, carrying out desorption drying treatment for 5 hours, fully plugging, and capping to obtain the freeze-dried powder A2.
Example 3
Accurately weighing 0.5g of compound Cy-Bestatin and 0.4g of lactose in a sterile environment, placing in a clean preparation container, adding 4ml of water for injection, stirring until the water is completely dissolved, adding 5ml of water for injection, and stirring uniformly to obtain a freeze-dried stock solution.
Filling the freeze-drying stock solution into a 10ml tube glass bottle, half plugging, and transferring into a freeze dryer for freezing treatment, wherein the specific freeze-drying process comprises the following steps: quickly freezing the freeze-dried stock solution to-25 ℃, lasting for 3 hours, vacuumizing to 10Pa, heating to-5 ℃ at the speed of 3 ℃ per hour, carrying out sublimation drying treatment for 20 hours, heating to 40 ℃ at the speed of 10 ℃ per hour, carrying out desorption drying treatment for 10 hours, fully plugging, and capping to obtain the freeze-dried powder A3.
Example 4
Accurately weighing 0.4g of compound Ep-Bestatin and 0.6g of mannitol in a sterile environment, putting the mixture into a clean preparation container, adding 4ml of water for injection, stirring until the mixture is completely dissolved, then adding the water for injection to 5ml, and stirring uniformly to obtain a freeze-dried stock solution.
Filling the freeze-drying stock solution into a 10ml tube glass bottle, half plugging, and transferring into a freeze dryer for freezing treatment, wherein the specific freeze-drying process comprises the following steps: quickly freezing the freeze-dried stock solution to-35 ℃, keeping the freeze-dried stock solution for 1.5 hours, vacuumizing to 10Pa, heating to-12 ℃ at the speed of 1 ℃ per hour, carrying out sublimation drying treatment for 12 hours, heating to 25 ℃ at the speed of 6 ℃ per hour, carrying out desorption drying treatment for 7 hours, fully plugging, and capping to obtain the freeze-dried powder A4.
Test example
The freeze-dried powder of the antitumor drug prepared in the above example was subjected to the following stability tests:
(1) high temperature detection
45 bottles of the finished product of the example were randomly picked and placed in a drug stability testing box. Standing at 60 deg.C for 10 days, and taking samples of 0, 5, and 10 days to test various indexes including appearance, solubility and clarity. The results are detailed in Table 3.
(2) High humidity detection
Randomly extracting 45 bottles of finished products of the examples, placing each bottle in a drug stability test box after each bottle is accurately weighed, placing the bottles for 10 days under the conditions of the temperature of 25 ℃ and the Relative Humidity (RH) of 90% +/-5%, and comparing sampling detection on the 5 th day and the 10 th day with samples on the 0 th day; the appearance, redissolution and clarity of the product were examined. The results are detailed in Table 4.
(3) Intense light detection
45 bottles of finished products of the examples are randomly selected, placed in a strong light stability test box of the medicine, placed for 10 days under the condition of the illumination of 4500 +/-500 Lx, sampled and detected on the 0 th, 5 th and 10 th days respectively, and the light stability of the products is examined by comparing indexes such as appearance property, redissolution property, clarity and the like. The results are detailed in Table 5.
TABLE 3
TABLE 4
TABLE 5
As can be seen from the results of tables 3-5 above, the lyophilized powder of an antitumor drug prepared by the method of the present invention has good high temperature stability, high humidity stability and stability under strong light irradiation.
The preferred embodiments of the present invention have been described above in detail, but the present invention is not limited thereto. Within the scope of the technical idea of the invention, many simple modifications can be made to the technical solution of the invention, including combinations of various technical features in any other suitable way, and these simple modifications and combinations should also be regarded as the disclosure of the invention, and all fall within the scope of the invention.
Claims (6)
1. The lyophilized powder of the antineoplastic containing ubenimex structure comprises a pharmaceutically active component and an excipient, and is characterized in that the mass ratio of the pharmaceutically active component to the excipient is 1: 0.5-6, wherein the drug active component is a prodrug derivative of ubenimex shown in formula (I),
wherein R in the formula (I) is selected from
2. The lyophilized powder of claim 1, wherein the mass ratio of the pharmaceutically active component to the excipient is 1: 0.8-2.
3. The lyophilized powder of claim 1, wherein the excipient is at least one of mannitol, glucose, and lactose.
4. A method of preparing a lyophilized powder of any of claims 1-3, comprising the steps of:
(1) stirring the active pharmaceutical ingredient, the excipient and the water for injection until the active pharmaceutical ingredient, the excipient and the water for injection are completely dissolved to obtain a freeze-dried stock solution;
(2) pre-freezing the freeze-dried stock solution at-25 to-40 ℃ for 1 to 3 hours, vacuumizing to 5 to 30Pa after freezing, heating to-5 to-15 ℃ at the speed of 1 to 3 ℃ per hour, carrying out sublimation drying treatment for 10 to 20 hours, heating to 20 to 40 ℃ at the speed of 5 to 10 ℃ per hour, and carrying out resolution drying treatment for 5 to 10 hours.
5. The method according to claim 4, wherein the volume ratio of the total amount of the pharmaceutically active ingredient and the excipient to the water for injection is 5-20: 100.
6. the method according to claim 5, wherein the volume ratio of the total amount of the pharmaceutically active ingredient and the excipient to the water for injection is 8-15: 100.
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