WO2015154677A1 - Composition pharmaceutique et son utilisation - Google Patents

Composition pharmaceutique et son utilisation Download PDF

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Publication number
WO2015154677A1
WO2015154677A1 PCT/CN2015/076102 CN2015076102W WO2015154677A1 WO 2015154677 A1 WO2015154677 A1 WO 2015154677A1 CN 2015076102 W CN2015076102 W CN 2015076102W WO 2015154677 A1 WO2015154677 A1 WO 2015154677A1
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solution
paclitaxel
lapachone
lpc
pharmaceutical composition
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Chinese (zh)
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钱锋
高金明
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Tsinghua University
University of Texas System
University of Texas at Austin
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Tsinghua University
University of Texas System
University of Texas at Austin
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers

Definitions

  • the present invention relates to the field of medicine, and in particular to pharmaceutical compositions and uses thereof, and more particularly to pharmaceutical compositions, uses of the pharmaceutical compositions in the preparation of medicaments, and methods of preparing micelles.
  • Beta-lapachone is a novel, promising anticancer drug that causes apoptosis in a variety of cancer cells, especially in cancer cells that overexpress quinone oxidoreductase (NQO1), such as breast cancer. Apoptosis is particularly evident in cells, prostate cancer cells, pancreatic cancer, lung cancer cells, and leukemia cells. --lapa is poorly soluble, with a solubility in water of only 0.038 mg/ml and a high effective dose (>500 mg).
  • ⁇ -lapachone and hydroxypropyl- ⁇ -cyclodextrin can greatly improve its solubility and bioavailability, but due to high dose of hydroxypropyl
  • the basal- ⁇ -cyclodextrin HP ⁇ -CD
  • ⁇ -lapach has a weak binding ability to albumin, and it cannot be effectively formed by forming an albumin complex like paclitaxel.
  • the present invention aims to solve at least one of the technical problems in the related art to some extent. To this end, it is an object of the present invention to provide a means for effectively treating or preventing cancer.
  • the present invention has been completed based on the following findings of the inventors: At present, many drugs have low bioavailability in the body, and side effects are large. One of the important reasons is that the water solubility of the drug is poor, the dosage is large, and there is no targeting effect. Can not effectively act on the lesion location, some drugs may also cause damage to normal human tissues; some poorly water-soluble drugs are also very easy to crystallize, unable to form a physically stable pharmaceutical preparation.
  • the use of polymer micelles as a drug carrier can effectively solubilize certain poorly water-soluble drugs. However, for a drug that is too fast in crystallization, the drug quickly forms crystals and escapes from the micelles, and a stable system cannot be formed, so that it cannot be effectively applied.
  • the invention provides a pharmaceutical composition.
  • the pharmaceutical composition comprises: an active ingredient; and a crystallization inhibitor.
  • the crystallization inhibitor can effectively inhibit the crystallization of the active ingredient, thereby significantly increasing the bioavailability of the active ingredient.
  • the active ingredient is a drug molecule having a fast crystallization rate.
  • the expression "the drug molecule with fast crystallization rate” as used herein refers to a drug having a crystallization ability of "Class I", that is, the molten drug is crystallized during the cooling process in DSC, and the literature is referred to as "JABaird”. , B. Van Eerdenbrugh, and LSTaylor. A classification system to assess the crystallization tendency of organic molecules from undercooled melts. Journal of Pharmaceutical Sciences. 99: 3787-3806 (2010).
  • the active ingredient is a drug molecule having a low solubility.
  • low solubility drug means that the dose of the drug cannot be dissolved by a clinically acceptable volume of aqueous solution.
  • the solubility is 0.38 mg/mL, but the dose is greater than 500 mg, and the volume of the aqueous solution preparation is too large to be clinically administered intravenously.
  • the crystallization inhibitor is a drug molecule which can inhibit the crystallization of the active ingredient and has a pharmacological synergistic effect with the active ingredient.
  • the expression "the drug molecule which can inhibit the crystallization of the active ingredient and has a pharmacological synergistic effect with the active ingredient” as used herein means that the crystallization inhibitor has a strong physical interaction with the active ingredient, and a substance having a higher glass transition temperature Tg (greater than 20 ° C), wherein the quantitative measurement of the physical interaction can be performed by the Flory-Huggins equation interaction parameter x, with a melting point reduction
  • the interaction parameter of the crystallization inhibitor and the active ingredient measured by the method is x ⁇ 0.
  • the active ingredient is at least one selected from the group consisting of ⁇ -lapachone, ⁇ -lapachone analogs, derivatives, or prodrugs.
  • Applicants believe that any known analogs, derivatives, or prodrugs of ⁇ -lapachone, ⁇ -lapachone, and analogs, derivatives, or prodrugs of ⁇ -lapachone may be used.
  • the types can be referred to the following documents: Xinpeng Ma, Xiumei Huang, et al, Prodrug Strategy to Achieve Lyophilizable, High Drug Loading Micelle Formulations Through Diester Derivatives of ⁇ -Lapachone, Adv. Healthcare Mater. 2014, DOI: 10.1002/adhm.201300590.
  • the crystallization inhibitor is at least one selected from the group consisting of paclitaxel and paclitaxel analogs/derivatives.
  • the paclitaxel analog/derivative may be docetaxel, cabazitaxel or the like.
  • the active ingredient is ⁇ -lapachone
  • the crystallization inhibitor is paclitaxel
  • the weight ratio of ⁇ -lapach and the paclitaxel is 1:0.1 ⁇ 3.
  • the weight ratio of the paclitaxel to the ⁇ -lapachone is 1:1 and 1:3.
  • the effect of paclitaxel on the inhibition of ⁇ -lapachone crystallization is remarkable, and the bioavailability of ⁇ -lapachone is significantly improved, and the synergistic therapeutic effect between the two is obvious.
  • the pharmaceutical composition is in various micelles, albumin nano preparations, capsules, pills In the form of a dose, a tablet, a granule, an oral liquid, an internal cream, an aerosol or a spray. Thereby, administration is easy.
  • the pharmaceutical composition is in the form of micelles and the micelles are formed from a polyethylene glycol polylactic acid block copolymer.
  • the encapsulation efficiency of the active ingredient in the micelle is from 11.7% to 100%.
  • the bioavailability of the drug is high, and the effect of treating or preventing cancer, especially lung cancer, is remarkable.
  • the invention provides the use of a pharmaceutical composition as hereinbefore described in the manufacture of a medicament for the treatment or prevention of cancer, preferably lung cancer, more preferably non-small cell lung cancer.
  • the invention also provides a method of preparing a micelle.
  • the method comprises: (1) mixing a paclitaxel solution, a ⁇ -lapachone solution, and an amphiphilic polymer solution, wherein the paclitaxel solution, ⁇ -lapachone solution, and amphipathicity
  • the polymer solution is an organic solution; (2) evaporating the mixture obtained in the step (1) to form a film, preferably evaporating to form a film within 5 minutes; (3) performing ultrasonic treatment after adding water to the film; (4)
  • the sonicated product obtained in the step (3) is filtered to obtain the micelle.
  • the method can be quickly and efficiently prepared by using the method of the invention, and the operation is simple, easy to control, and has no special requirements on the equipment, and is suitable for large-scale production.
  • paclitaxel can effectively inhibit ⁇ -lapachone crystallization, thereby significantly increasing the drug loading and bioavailability of ⁇ -lapach, and the formed micelles have good stability and can be effectively used for treating or preventing cancer, especially It is lung cancer.
  • the paclitaxel solution is a solution of paclitaxel in acetonitrile.
  • the concentration of the paclitaxel solution is 4 mg/ml.
  • the ⁇ -lapachone solution is a solution of ⁇ -lapachone in acetonitrile.
  • the concentration of the ⁇ -lapachone solution is 4 mg/ml.
  • the amphiphilic polymer is a polyethylene glycol polylactic acid block copolymer. Therefore, it is safe and non-toxic and can be effectively used for clinical treatment.
  • the amphiphilic polymer solution is a solution of an amphiphilic polymer in acetonitrile.
  • the concentration of the amphiphilic polymer solution is 36 mg/ml.
  • the sonication is performed at 300 watts for 5 minutes. Thereby, the formation of micelles is facilitated, and the efficiency of preparing micelles is improved.
  • the filtration is carried out using a nylon filter having a pore size of 0.45 ⁇ m.
  • Figure 1a is a graph showing the results of DSC detection of LPC during cooling at a cooling rate of 10 ° C / min.
  • Figure 1b is a graph showing DSC results of sample powders 9/1 LPC/PTX, 7/3 LPC/PTX, 5/5 LPC/PTX, and LPC at a heating rate of 1 ° C/min;
  • FIG. 2 shows a chromatogram of a mixed solution of an LPC solution, a PTX solution, and LPC and PTX, according to an embodiment of the present invention, wherein
  • 2A is a chromatogram of a mixed solution of LPC solution (LPC) and LPC and PTX (5/5LPC/PTX) at a detection wavelength of 257 nm.
  • LPC LPC solution
  • PTX 5/5LPC/PTX
  • 2B is a chromatogram of a PTX solution (PTX) and a mixed solution of LPC and PTX (5/5LPC/PTX) at a detection wavelength of 227 nm;
  • FIG. 3 shows an LPC concentration-time curve of a supersaturated solution of an LPC supersaturated solution and a mixture of LPC and PTX, in accordance with one embodiment of the present invention
  • FIG. 4 shows a scanning electron micrograph of a sample precipitated from an LPC precipitated sample and a mixture of LPC and PTX, according to one embodiment of the present invention, wherein
  • Figure 4A is a scanning electron micrograph of a sample of LPC precipitated
  • 4B is a scanning electron micrograph of a precipitated sample of a mixture of LPC and PTX;
  • Figure 5 shows a powder X-ray diffraction spectrum of an LPC precipitated sample, a PTX precipitated sample, and a precipitated sample of LPC and PTX mixture (LPC/PTX), in accordance with one embodiment of the present invention
  • Figure 6 shows a photograph of different proportions of micelles in accordance with one embodiment of the present invention.
  • Figure 7 shows the results of DLS detection of different proportions of micelles according to an embodiment of the present invention, wherein
  • Figure 7A shows the results of DLS detection of LM micelles.
  • Figure 7B shows the results of DLS detection of 7L3PM micelles.
  • Figure 7C shows the results of DLS detection of 5L5PM micelles
  • Figure 8 shows a transmission electron micrograph of different proportions of micelles in accordance with one embodiment of the present invention.
  • Figure 9 shows a nuclear magnetic resonance spectrum of different proportions of micelles in accordance with one embodiment of the present invention.
  • Figure 10 shows an in vitro drug release profile of different proportions of micelles, in accordance with one embodiment of the present invention, wherein
  • Figure 10A is a drug release curve when phosphate buffer is used as a release medium
  • Fig. 10B is a drug release curve when salicylate is used as a release medium.
  • the invention provides a pharmaceutical composition.
  • the medicament comprises: an active ingredient; and a crystallization inhibitor.
  • the crystallization inhibitor can effectively inhibit the crystallization of the active ingredient, thereby significantly increasing the bioavailability of the active ingredient.
  • the active ingredient is a drug molecule having a fast crystallization rate.
  • the expression "the drug molecule with fast crystallization rate” as used herein refers to a drug having a crystallization ability of "Class I", that is, the molten drug is crystallized during the cooling process in DSC, and the literature is referred to as "JABaird”. , B. Van Eerdenbrugh, and LSTaylor. A classification system to assess the crystallization tendency of organic molecules from undercooled melts. Journal of Pharmaceutical Sciences. 99: 3787-3806 (2010).
  • the active ingredient is a drug molecule having a low solubility.
  • low solubility drug means that the dose of the drug cannot be dissolved by a clinically acceptable volume of aqueous solution.
  • the solubility is 0.38 mg/mL, but the dose is >500 mg, and the volume of the aqueous solution preparation is too large to be clinically realized.
  • the crystallization inhibitor is a drug molecule which can inhibit the crystallization of the active ingredient and has a pharmacological synergistic effect with the active ingredient.
  • the expression "the drug molecule which can inhibit the crystallization of the active ingredient and has a pharmacological synergistic effect with the active ingredient” as used herein means that the crystallization inhibitor has a strong physical interaction with the active ingredient, and It has its own higher glass transition temperature Tg (greater than 20 ° C), in which physical interaction can be qualitatively verified by spectroscopy, such as infrared, Raman, etc., quantitative measurement can use the Flory-Huggins formula (Flory-Huggins equation)
  • Tg glass transition temperature
  • the active ingredient is at least one selected from the group consisting of ⁇ -lapachone, ⁇ -lapachone analogs, derivatives, or prodrugs.
  • Applicants believe that any known analog, derivative, or prodrug of ⁇ -lapachone, ⁇ -lapachone, and analogs, derivatives, or prodrugs of ⁇ -lapachone may be used.
  • the types can be referred to the following documents: Xinpeng Ma, Xiumei Huang, et al, Prodrug Strategy to Achieve Lyophilizable, High Drug Loading Micelle Formulations Through Diester Derivatives of ⁇ -Lapachone, Adv. Healthcare Mater. 2014, DOI: 10.1002/adhm.201300590.
  • the crystallization inhibitor is at least one selected from the group consisting of paclitaxel and paclitaxel analogs/derivatives.
  • the paclitaxel analog/derivative may be docetaxel or cabazitaxel or the like.
  • ⁇ -Lappa is poorly soluble and has a solubility in water of only 0.038 mg/ml.
  • HP ⁇ -CD hydroxypropyl- ⁇ -cyclodextrin
  • ⁇ -lapach has a weak binding ability to albumin, and it cannot be effectively formed by forming an albumin complex like paclitaxel.
  • ⁇ -lapachone has a very high crystallization rate and is easily detached from the carrier when it is delivered to the body by a drug carrier, and the bioavailability is low.
  • the active ingredient is ⁇ -lapachone
  • the crystallization inhibitor is paclitaxel
  • the weight ratio of ⁇ -lapachone to the paclitaxel is 1:0.1. ⁇ 3.
  • the crystallization inhibitor paclitaxel can effectively inhibit the ⁇ -lapachone crystallization of the active ingredient, improve the stability of the system, the bioavailability of the active ingredient is remarkably improved, and ⁇ -lapach and paclitaxel have synergistic effects. To effectively treat or prevent cancer, especially The treatment effect on lung cancer is remarkable.
  • the weight ratio of the paclitaxel to the ⁇ -lapachone is 1:1 and 1:3.
  • the effect of paclitaxel on the inhibition of ⁇ -lapachone crystallization is remarkable, and the bioavailability of ⁇ -lapachone is significantly improved, and the synergistic therapeutic effect between the two is obvious.
  • the dosage form of the pharmaceutical composition is not particularly limited, and those skilled in the art can flexibly select according to actual conditions.
  • the pharmaceutical composition is in the form of a micelle, capsule, pill, tablet, granule, oral liquid, internal cream, aerosol or spray. Thereby, administration is easy.
  • Polymer micelles are attracting more and more attention as drug carriers.
  • the polymer micelles form a unique core-shell structure, the outer shell is formed by hydrophilic segments, and the inner core is formed by hydrophobic segments, which encapsulates the hydrophobic drug in the core of the micelle and protects the loaded drug.
  • the micelle size is generally 10-100 nm, which makes it possible to escape the phagocytosis of the human reticuloendothelial system (RES) and the environment of others, and at the same time increase the high permeability and retention effect (EPR) of solid tumors.
  • RES human reticuloendothelial system
  • EPR high permeability and retention effect
  • the pharmaceutical composition is in the form of micelles and the carrier of the micelles is a polyethylene glycol polylactic acid diblock copolymer (PEG-PLA).
  • PEG-PLA polyethylene glycol polylactic acid diblock copolymer
  • the active ingredient can be prevented from being excreted by the human reticuloendothelial system and degraded into non-toxic monomers, and the hydrophilic segment of PEG has the advantages of being easily soluble in water, easy to flow and low toxicity, and can be achieved. The effect of long loops.
  • the micellar system can effectively increase the drug loading and bioavailability of the active ingredient, thereby better functioning in treating or preventing cancer.
  • the encapsulation efficiency of the active ingredient in the micelle is from 11.7% to 100%.
  • the bioavailability of the drug is high, and the effect of treating or preventing cancer, especially lung cancer, is remarkable.
  • the invention provides the use of a pharmaceutical composition as hereinbefore described in the manufacture of a medicament for the treatment or prevention of cancer, preferably lung cancer, more preferably non-small cell lung cancer.
  • the invention also provides a method of preparing a micelle. According to an embodiment of the invention, the method comprises the steps of:
  • the paclitaxel solution, the ⁇ -lapachone solution, and the amphiphilic polymer solution are mixed, wherein the paclitaxel solution, the ⁇ -lapachone solution, and the amphiphilic polymer solution are all organic solutions.
  • the paclitaxel solution is a solution of paclitaxel in acetonitrile.
  • the concentration of the paclitaxel solution is 4 mg/ml.
  • the ⁇ -lapachone solution is a solution of ⁇ -lapachone in acetonitrile.
  • the concentration of the ⁇ -lapachone solution is 4 mg/ml.
  • the amphiphilic polymer is a polyethylene glycol polylactic acid diblock copolymer. Therefore, it is safe and non-toxic and can be effectively used for clinical treatment.
  • the amphiphilic polymer solution is a solution of an amphiphilic polymer in acetonitrile.
  • the concentration of the amphiphilic polymer solution is 36 mg/ml.
  • the mixture obtained in the step (1) is evaporated to form a film. According to an embodiment of the present invention, the mixture obtained in the step (1) is evaporated to form a film within 5 minutes.
  • Ultrasonic treatment is carried out after adding water to the film.
  • the sonication is performed at 300 watts for 5 minutes. Thereby, it is advantageous for dispersion and improves the efficiency of preparing micelles.
  • the sonicated product obtained in the step (3) is filtered to obtain the micelle.
  • the filtration is carried out using a nylon filter having a pore size of 0.45 ⁇ m.
  • the method can be quickly and efficiently prepared by using the method of the invention, and the operation is simple, easy to control, and has no special requirements on the equipment, and is suitable for large-scale production.
  • paclitaxel can effectively inhibit ⁇ -lapachone crystallization, thereby significantly increasing the drug loading and bioavailability of ⁇ -lapach, and the formed micelles have good stability and can be effectively used for treating or preventing cancer, especially It is lung cancer.
  • DSC differential scanning calorimetry
  • the sample powder and LPC obtained above were respectively placed in an aluminum pan covered with a pinhole, and the aluminum pan was placed on a sample stage of a DSC Q2000 Differential Scanning Calorimeter (TA Instruments, New Castle, DE, USA), first The sample in the aluminum pan is preheated to 105 degrees Celsius to remove the remaining solvent and moisture, then the sample is heated to above the melting point of LPC at a temperature increase rate of 1 degree Celsius/minute or 10 degrees Celsius/minute, and then quenched to 0 degrees Celsius. Wherein, the temperature at which all crystals are completely melted is referred to as T end .
  • the partial test results are shown in Fig. 1.
  • Fig. 1a is a DSC test result of LPC during cooling at a cooling rate of 10 ° C / min.
  • the upper left side of Fig. 1a is a polarizing microscope photograph of LPC;
  • Fig. 1b is The DSC test results of the sample powders 9/1 LPC/PTX, 7/3 LPC/PTX, 5/5 LPC/PTX, and LPC at a heating rate of 1 degree Celsius/minute.
  • Fig. 2A is a chromatogram of a mixed solution of LPC solution (LPC) and LPC and PTX (5/5LPC/PTX) at a detection wavelength of 257 nm
  • Fig. 2B shows a detection wavelength of 227 nm. Chromatogram of PTX solution (PTX) and mixed solution of LPC and PTX (5/5LPC/PTX).
  • LPC 20 mg of LPC was dissolved in 4 ml of methanol to obtain a LPC solution having a concentration of 5 mg/ml, and then 20 mg of a mixture of LPC and PTX was dissolved in 4 ml of methanol to obtain a mixed solution having an LPC concentration of 5 mg/ml.
  • PBS phosphate buffer solution
  • the concentration of LPC in the two supersaturated solutions was measured by HLPC at 2 min, 5 min, 10 min, 15 min, 20 min and 25 min, respectively, and the LPC concentration-time curve was plotted (see Fig. 3).
  • the chromatographic detection parameters were the same as in Example 2, and each sample was subjected to three repeated experiments.
  • the precipitates in the above supersaturated solution were collected and dried, respectively, using a FEI Quanta 200 Scanning Electron Microscope (Czech) and a powder X-ray diffractometer (PANalytical X'pert Powder X-ray diffractometer, Almelo, The Netherlands). The surface morphology and crystallization of the precipitated samples were observed. Scanning electron microscopy (SEM) photographs of LPC precipitated samples are shown in Figure 4A.
  • the LPC precipitated sample showed intact crystals, and in the presence of PTX, the morphology of the LPC crystal was different from that before, and the LPC and PTX mixture precipitated samples could not form intact crystals, indicating that PTX can inhibit LPC crystallization. It can also be seen from the results of Fig. 5 that the LPC crystallinity is significantly lowered when PTX is present. In summary, it is shown that PTX can effectively inhibit LPC crystallization under the condition of aqueous solution.
  • ⁇ -lapachone 40 mg was dissolved in 10 ml of acetonitrile, sonicated for 2 minutes to obtain a ⁇ -lapachone solution; 40 mg of paclitaxel (PTX) was dissolved in 10 ml of acetonitrile, and sonicated for 2 minutes.
  • a paclitaxel solution was obtained; 36 mg/ml of a polyethylene glycol polylactic acid block copolymer (PEG-PLA) aqueous solution was frozen, then sonicated for 30 minutes, and then lyophilized to dissolve 360 mg of the freeze-dried PEG-PLA in 10 ml.
  • the acetonitrile was sonicated for 2 minutes to obtain a polyethylene glycol polylactic acid block copolymer solution.
  • the ⁇ -lapachone solution, the paclitaxel solution and the polyethylene glycol polylactic acid block copolymer solution obtained above were mixed according to the ratios shown in Table 1, and the obtained mixture was sonicated for 2 minutes, at 5 Rotate to form a film in a minute, then add 10 ml of pure water at a temperature of 60 ° C to the obtained film, and after sonicating for 5 minutes, remove the unencapsulated micelle by a nylon filter having a pore size of 0.45 ⁇ m.
  • Paclitaxel and ⁇ -lapaquinone obtained different ratios of micelles, respectively. Photographs of different ratios of micelle solutions are shown in Figure 6.
  • the weight of the PE tube was weighed, and 0.5 ml of the micelle solution was added to a known weight of PE tube. After lyophilization, the weight of the lyophilized product was accurately weighed to calculate the packing density of the micelle.
  • Encapsulation rate mass of drug loaded in micelle / mass of drug added to micellar system ⁇ 100%
  • the particle size of the micelle is 40-50 nm, and it has been reported that this particle size range can effectively enhance the EPR effect.
  • TEM Transmission electron microscopy
  • Fig. 10A From the results of Fig. 10A, it can be seen that the presence of PTX in the presence of phosphate buffer as a release medium has little effect on the release of LPC. In 3 hours, the cumulative release of LPC in both LM and 5L5PM micelles reaches 50. %, while in the same time range, PTX is not released from PM micelles, depending on PM physicochemical properties. Compared with PM micelles, LPC can promote the release of PTX to some extent in 5L5PM micelles. It can be seen from Fig.
  • the toxicity test of the paclitaxel-resistant A549 cell line of the micelles prepared in Example 5 was carried out according to the following procedure:
  • Paclitaxel-resistant A549 cells were plated in 96-well black matrix (2000 cells/well). After 24 hours of culture, the old medium in 96-well plates was discarded and 200 ⁇ L of medium containing different drug micelle concentrations was added. The cells were cultured for 4 hours, and then cultured for 7 days after replacing 200 ⁇ L of fresh medium. After 7 days, the old medium was discarded, the cells were washed with 200 ⁇ L of PBS, and all PBS was discarded.
  • the 96-well plate was placed in a -80 ° C refrigerator for 2 hours, and after the cells were completely thawed, 200 ⁇ L of 1:1000 Hoechst 33258 and TNE (1 mM EDTA, 2 M NaCl) were added per well.
  • the dye solution of 10 mM Tris, pH 7.5) was stored at room temperature in the dark for 2 hours, and the plate was read by a Perkin Elmer instrument.
  • the excitation light was 356 nm and the emission light was 458 nm.
  • Example 5 The therapeutic effect of the micelles prepared in Example 5 on a paclitaxel-resistant tumor animal model was carried out according to the following procedure:
  • mice Female athymic nude mice (6-8weeks, 18-22g) were injected subcutaneously right hind leg 5 ⁇ 10 6-derived paclitaxel resistant human A549 NSCLC. When the tumor grew to approximately 200 mm 3 , the animals were re-randomized into groups of 5 animals each. The animals were administered once a week in the tail vein, and both the paclitaxel micelles and the composite micelles were administered in an amount of PTX contained therein, and PTX 30 mg/kg was administered three times in total. The blank control group was given an equal volume of blank micelles. After administration, the size of the tumor and the body weight of the animal were measured and weighed once every two days. The length (L) and width (W) of the tumor were measured using a vernier caliper, and the volume of the tumor was equal to L ⁇ W 2 /2.
  • the relative tumor inhibition rate of the PM group (PTX 30 mg/kg) against paclitaxel-resistant A549 human lung cancer xenograft nude mice model was 30%, and the equivalent dose of PTX was converted into 1L3PM.
  • the tumor inhibition rate was 95%.
  • the body weight changes of the PM group and the 1L3PM group did not fluctuate significantly.
  • the 1L3PM group was significantly better than the PM group in the paclitaxel-resistant A549 human lung cancer xenograft model, and no significant side effects were observed.
  • LPC and PTX composite nanomicelles have significant synergistic therapeutic effects on paclitaxel-resistant animal models.
  • the pharmaceutical composition of the present invention wherein the crystallization inhibitor is effective for inhibiting crystallization of the active ingredient, so that the bioavailability of the active ingredient in the pharmaceutical composition is very high.

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Abstract

La présente invention se rapporte à une composition pharmaceutique et à son utilisation, ladite composition pharmaceutique comprenant des principes actifs et un inhibiteur de cristallisation.
PCT/CN2015/076102 2014-04-08 2015-04-08 Composition pharmaceutique et son utilisation Ceased WO2015154677A1 (fr)

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