WO2021057007A1 - Agent à libération prolongée à l'échelle nanométrique de rapamycine et son procédé de préparation - Google Patents

Agent à libération prolongée à l'échelle nanométrique de rapamycine et son procédé de préparation Download PDF

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WO2021057007A1
WO2021057007A1 PCT/CN2020/082852 CN2020082852W WO2021057007A1 WO 2021057007 A1 WO2021057007 A1 WO 2021057007A1 CN 2020082852 W CN2020082852 W CN 2020082852W WO 2021057007 A1 WO2021057007 A1 WO 2021057007A1
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rapamycin
release agent
sustained
nano
preparation
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PCT/CN2020/082852
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严鹏科
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严鹏科
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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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection

Definitions

  • the invention relates to the technical field of rapamycin preparations, in particular to a rapamycin nano sustained-release agent and a preparation method thereof.
  • Tumor Cancer has become the number one killer that endangers human health. Although there are endless methods to treat tumors, the living conditions of most patients have not been greatly improved. Among the various treatment methods for tumors, chemotherapy is still the most commonly used option. Although chemotherapy drugs are widely used, their therapeutic effects on solid tumors are not exact. The fundamental problem is that traditional chemotherapeutic drugs cannot achieve effective therapeutic concentrations at the tumor site or cannot maintain sufficient time of action. Moreover, traditional chemotherapeutic drugs can kill normal cells indiscriminately, resulting in a variety of toxic side effects. The effect of chemotherapeutic drugs depends not only on the sensitivity of the drug, but also on the time of action of the drug at the tumor site and the accumulation of the drug at the tumor site. Therefore, the local application of chemotherapeutic drugs, especially local sustained release, has become a hot and difficult point in current tumor chemotherapy research.
  • Rapamycin was discovered in the soil of Easter Island in Chile in 1975. It is a hydrophobic macrolide immunosuppressant produced by streptomyces hygroscopicus. It has antifungal activity and is a white crystal with a relative molecular mass of 914.2. It is easily soluble in organic solvents such as formaldehyde, ethanol, acetone, chloroform, and almost insoluble in water.
  • Rapamycin is a powerful immunosuppressant with low toxicity. It inhibits the cell cycle G 0 and G 1 phases by combining with the corresponding immunophilin RMBP, and blocks G 1 from entering the S phase. It is widely used in transplantation surgery. in.
  • rapamycin also has anti-tumor effects, which can inhibit the growth of tumor cells such as kidney cancer, lymphoma, lung cancer, liver cancer, breast cancer, neuroendocrine cancer and gastric cancer in a concentration-dependent manner. Since 2007, two derivatives of rapamycin, tamsulolimus and everolimus, have been developed for the treatment of cancer. The research and application of rapamycin in tumor treatment has been increasing.
  • RAPA inhibits mammalian target of rapamycin (m TOR) receptors and affects various signal pathways of its transduction, thereby exerting various effects on tumors such as anti-angiogenesis, blocking cell cycle and promoting cell apoptosis.
  • m TOR mammalian target of rapamycin
  • Nano-preparation has a high degree of dispersibility and a huge surface area, which is beneficial to increase the contact time and contact area of the drug and the biofilm of the absorption site, and increase the solubility of the drug; the nanoparticle can enter the cell through the endocytosis mechanism and transport the general drug across the membrane. The mechanism is different, so it may increase the permeability of the drug to the biofilm.
  • Nano drug delivery system as an effective means to optimize drug efficacy has become a research hotspot in the fields of pharmacy and modern biomedicine.
  • Rapamycin is a hydrophobic drug and cannot be directly used for injection. It needs a certain organic solvent to dissolve it before injection, which is easy to cause adverse effects on the human body; the bioavailability of rapamycin in vivo is very low, and it is easy to cause failure to reach the diseased site It's already a problem.
  • phospholipids or cholesterones on the market as the carrier of nano-released rapamycin.
  • This type of carrier has a very high affinity with the human body, but due to the natural degradation rate of phospholipids or cholesterones in the blood Fast, so that the concentration of rapamycin at the site of action is low, and the targeting is insufficient.
  • one of the objectives of the present invention is to provide a rapamycin that can effectively control the sustained release rate of rapamycin, increase its residence time in tumor tissues, and prolong its half-life in plasma. Nanometer slow release agent.
  • the second object of the present invention is to provide a preparation method of the rapamycin nano sustained-release agent.
  • a rapamycin nano sustained-release agent which is made from the following raw materials in parts by weight: 1 part of rapamycin, 0.5-20 parts of soluble polymer carrier, 40-200 parts of organic solvent and 400-20000 Parts of the aqueous phase.
  • the nano slow-release agent forms a slow-release coating structure through the coating effect of a soluble high molecular polymer on rapamycin.
  • the coating structure is dispersed into nano-scale through the dispersibility of the organic solvent and the aqueous phase. Of coated particles.
  • the soluble high molecular polymer carrier is polyethylene glycol-2000, polyethylene glycol-4000, polyethylene glycol-10000, polyethylene glycol-15000, PLGA, PEO, PVP, polypropylene, poly One or two or more of amino acid, polysorbate and polyoxyethylene ester fatty acid.
  • the sustained-release agent formed by the polymer carrier has a relatively longer hydrophilic time, which can increase the sustained-release time of the injection formed by rapamycin in the body and prolong the half-life.
  • the soluble high molecular polymer carrier is a methoxy polyethylene glycol block copolymer.
  • the soluble high molecular polymer carrier is mPEG-PLA with a molecular weight of 3000-20000. It is a block copolymer of methoxy polyethylene glycol and polylactic acid.
  • the organic solvent is one or more of absolute ethanol, dichloromethane, acetone and methanol.
  • the organic solvent needs to have better solubility for rapamycin and the soluble high molecular polymer carrier, and at the same time have better dispersibility in water, and be miscible with water. That is, the organic solvent is soluble in water.
  • the aqueous phase liquid is one or two of distilled water, physiological saline, cell culture fluid, body fluid, tissue fluid, buffer, or glucose injection.
  • the aqueous phase liquid provides a better dispersion medium for the organic phase. Through the dispersion of the hydrophilic soluble polymer carrier and the organic solvent, the dispersibility of rapamycin in the aqueous phase can be effectively improved to form Nano-level particles.
  • the raw material also includes a freeze-dried protective agent.
  • the lyoprotectant is one or more of lactose, glucose, mannitol or sucrose.
  • a preparation method of the above-mentioned rapamycin nano sustained-release agent includes the following steps:
  • micellar solution ( 4) Centrifuge for 5-120min, take the supernatant, filter with 0.22-0.45 ⁇ m membrane to obtain micellar solution;
  • micellar solution Freeze-dry the micellar solution to obtain a rapamycin nano-sustained release agent.
  • the rapamycin bulk drug and the soluble high molecular polymer carrier are dispersed by an organic solvent to form a uniformly dispersed organic phase. Then, by slowly releasing the organic phase into the aqueous phase, the difference in dissolution rate and the agitation of the aqueous phase digestion cause the rapamycin and the soluble high molecular polymer to form nano-scale micelles.
  • step 2) the stirring speed is 500-800 rpm; in step 4), the centrifugal speed is 4000-8000 rpm.
  • step 4 5-10 g of lyoprotectant is added to every 100 mL of micellar solution.
  • the invention provides a rapamycin nano sustained-release agent, which finally forms a micelle-like nano particle structure in an aqueous phase through the coating effect of a soluble high molecular polymer and the solubilization and dispersion effect of an organic solvent.
  • the micellar nanoparticle structure improves the sustained release of rapamycin in plasma, tissue fluid or further in the digestive tract, and its half-life is relatively controllable, allowing rapamycin to reach the affected area.
  • the rapamycin nano sustained-release agent provided by the present invention has a nano-micelle structure with a particle size of 10-200nm, a drug loading amount of 0.1-20%, and an encapsulation rate of over 80%. It has uniformity and Stable particle size distribution, stable encapsulation rate and drug loading, and low risk to blood vessels; the rapamycin nano-released agent has stable encapsulation rate and drug loading, and has a better tumor targeting effect;
  • the half-life of the rapamycin nano sustained-release agent in the blood can be as high as more than 50 hours, and it can reach the affected area of the tumor directly. With continuous medication, the tumor regression rate can reach 50%.
  • Figure 1 shows the appearance of the formulations of Examples 1-5;
  • Figure 2 is a characterization diagram of the rapamycin nano sustained-release agent of Example 4.
  • Fig. 3 is a graph of the in vitro anti-tumor test results of the rapamycin nano-sustained release agent of Example 4;
  • Figure 4 is a diagram showing the results of in vivo targeting of the rapamycin nano sustained-release agent of Example 4.
  • Fig. 5 is a diagram showing the anti-tumor effect of the rapamycin nano sustained-release agent of Example 4 in vivo.
  • a rapamycin nano sustained-release agent which is made from the following raw materials in parts by weight: 1 part of rapamycin, 0.5-20 parts of soluble polymer carrier, 40-200 parts of organic solvent and 400-20000 Parts of the aqueous phase.
  • the application uses the coating effect of the soluble polymer carrier and the dispersion effect of the organic solvent to coat rapamycin in it to form micelles, which are slowly released into the aqueous phase to form nano-sized particles.
  • the structure is filtered and lyophilized to obtain a rapamycin nano-sustained release agent that can be used for injection.
  • the soluble high molecular polymer carrier is preferably a methoxy polyethylene glycol block copolymer, that is, it has a methoxy end group that can have better compatibility with rapamycin.
  • it is an mPEG-PLA block copolymer
  • the molecular weight is preferably 2000-20000 to form micelles, thereby forming nano-sustained-release agent particles with high encapsulation efficiency and an average particle size in the nm level.
  • Examples 1-10 all use mPEG-PLA copolymers, wherein the molecular weight of mPEG is 2000, the molecular weight of PLA is 2000, and the total molecular weight is 4000.
  • the residence time of the rapamycin nano-released agent in the tumor is 24-48h; the half-life in the blood is more than 52h.
  • the rapamycin nano-released agent has an injection amount of rapamycin based on the effective ingredient. Above 10 ⁇ g/mL, the tumor tissue will disappear by at least 50% after continuous medication.
  • the preparation method of the rapamycin nano sustained-release agent includes the following steps:
  • micellar solution ( 4) Centrifuge for 5-120min, take the supernatant, filter with 0.22-0.45 ⁇ m membrane to obtain micellar solution;
  • micellar solution Freeze-dry the micellar solution to obtain a rapamycin nano-sustained release agent.
  • the micelles with small particle size are formed by physical force through the method of stirring and dispersing; the final method is centrifugation, The free rapamycin in the micellar solution is removed, thereby obtaining a rapamycin nano-release drug with low blood health risk.
  • the carrier of the rapamycin nano sustained-release agent can be degraded under natural physiological conditions, thereby being excreted from the body through metabolism, and will not produce irritation or foreign body reaction to the body.
  • a rapamycin nano sustained-release agent made of the following components: 5 mg rapamycin, 10 mg mPEG-PLA block polymer, 1 mL acetone and 50 mL PBS buffer;
  • the preparation method includes the following steps:
  • micellar solution ( 4000 r/min for 30 min, take the supernatant, filter and sterilize with a 0.22 ⁇ m pore size microporous membrane to obtain a micellar solution;
  • micellar solution Freeze-dry the micellar solution to obtain a rapamycin nano-sustained release agent.
  • a rapamycin nano sustained-release agent made of the following components: 5 mg rapamycin, 20 mg mPEG-PLA block polymer, 1 mL acetone and 50 mL PBS buffer;
  • the preparation method includes the following steps:
  • micellar solution ( 4) Centrifuge at 5000 r/min for 30 min, take the supernatant, filter and sterilize with a 0.22 ⁇ m pore size microporous membrane to obtain a micellar solution;
  • micellar solution Freeze-dry the micellar solution to obtain a rapamycin nano-sustained release agent.
  • a rapamycin nano sustained-release agent made of the following components: 5 mg rapamycin, 40 mg mPEG-PLA block polymer, 1 mL acetone and 50 mL PBS buffer;
  • the preparation method includes the following steps:
  • micellar solution ( 4) Centrifuge at 5000 r/min for 30 minutes, take the supernatant, filter and sterilize with a 0.22 ⁇ m pore size microporous membrane to obtain a micellar solution;
  • micellar solution Freeze-dry the micellar solution to obtain a rapamycin nano-sustained release agent.
  • a rapamycin nano sustained-release agent made of the following components: 5 mg rapamycin, 50 mg mPEG-PLA block polymer, 1 mL acetone and 50 mL PBS buffer;
  • the preparation method includes the following steps:
  • micellar solution ( 4) Centrifuge at 5000 r/min for 30 min, take the supernatant, filter and sterilize with a 0.22 ⁇ m pore size microporous membrane to obtain a micellar solution;
  • micellar solution Freeze-dry the micellar solution to obtain a rapamycin nano-sustained release agent.
  • a rapamycin nano sustained-release agent made of the following components: 5 mg rapamycin, 60 mg mPEG-PLA block polymer, 1 mL acetone and 50 mL PBS buffer;
  • the preparation method includes the following steps:
  • micellar solution ( 4) Centrifuge at 5000 r/min for 30 minutes, take the supernatant, filter and sterilize with a 0.22 ⁇ m pore size microporous membrane to obtain a micellar solution;
  • micellar solution Freeze-dry the micellar solution to obtain a rapamycin nano-sustained release agent.
  • a rapamycin nano sustained-release agent made of the following components: 10 mg rapamycin, 90 mg mPEG-PLA block polymer, 1 mL acetone and 100 mL PBS buffer;
  • the preparation method includes the following steps:
  • micellar solution ( 4000 r/min for 30 minutes, take the supernatant, filter and sterilize with a 0.22 ⁇ m pore size microporous filter membrane to obtain a micellar solution;
  • micellar solution Freeze-dry the micellar solution to obtain a rapamycin nano-sustained release agent.
  • a rapamycin nano sustained-release agent which is made of the following components: 100 mg rapamycin, 900 mg mPEG-PLA block polymer, 7 mL acetone, 10 mL PBS buffer and 0.5 g lactose;
  • the preparation method includes the following steps:
  • micellar solution ( 4000 r/min for 30 minutes, take the supernatant, filter and sterilize with a 0.22 ⁇ m pore size microporous filter membrane to obtain a micellar solution;
  • micellar solution 5) Add lactose to the micellar solution, aseptically filter with a 0.22 ⁇ m pore filter membrane, freeze-dry, and obtain a rapamycin nano-sustained release agent.
  • a rapamycin nano sustained-release agent which is made of the following components: 150 mg rapamycin, 100 mg mPEG-PLA block polymer, 7 mL acetone, 100 mL PBS buffer and 5 g lactose;
  • the preparation method includes the following steps:
  • micellar solution ( 4000 r/min for 30 minutes, take the supernatant, filter and sterilize with a 0.22 ⁇ m pore size microporous filter membrane to obtain a micellar solution;
  • micellar solution 5) Add lactose to the micellar solution, aseptically filter with a 0.22 ⁇ m pore filter membrane, freeze-dry, and obtain a rapamycin nano-sustained release agent.
  • a rapamycin nano sustained-release agent made of the following components: 100 mg rapamycin, 1000 mg mPEG-PLA block polymer, 7 mL acetone, 100 mL PBS buffer and 5 g lactose;
  • the preparation method includes the following steps:
  • micellar solution ( 4000 r/min for 30 minutes, take the supernatant, filter and sterilize with a 0.22 ⁇ m pore size microporous filter membrane to obtain a micellar solution;
  • micellar solution 5) Add lactose to the micellar solution, aseptically filter with a 0.22 ⁇ m pore filter membrane, freeze-dry, and obtain a rapamycin nano-sustained release agent.
  • a rapamycin nano sustained-release agent which is made of the following components: 50 mg rapamycin, 500 mg mPEG-PLA block polymer, 7 mL acetone, 50 mL PBS buffer and 2.5 g lactose;
  • the preparation method includes the following steps:
  • micellar solution ( 4000 r/min for 30 minutes, take the supernatant, filter and sterilize with a 0.22 ⁇ m pore size microporous filter membrane to obtain a micellar solution;
  • micellar solution 5) Add lactose to the micellar solution, aseptically filter with a 0.22 ⁇ m pore filter membrane, freeze-dry, and obtain a rapamycin nano-sustained release agent.
  • the appearance evaluation criteria to maintain the original volume, no collapse, no shrinkage, uniform color, no variegation, and fine texture; the appearance is shown in Figure 1, and from left to right are the preparations of Examples 1-5 . ...
  • Average particle size Malvern laser particle size analyzer is used to measure the particle size and particle size distribution of nanoparticles. The principle is to use the characteristics of light scattering and light diffraction when the particles are irradiated by light, and the light scattering intensity and diffraction intensity are compared with the particles. The principle related to size and optical characteristics is used to determine the particle size.
  • Figure 2A is a mimic diagram of micelles of the rapamycin nano sustained-release agent of Example 4, in which the spherical shape is the active ingredient rapamycin, and the linear part is the mPEG-PLA block polymer;
  • Figure 2B is a particle size distribution diagram of rapamycin nano sustained-release agent;
  • Figure 2C is a TEM image of rapamycin nano sustained-release agent.
  • Figure 2D is the Zeta potential diagram of the rapamycin nano-sustained release agent.
  • Encapsulation rate The encapsulation rate is better than 80%.
  • the drug content was determined by high performance liquid chromatography with methanol-acetonitrile-water (volume ratio 43:40:17) as mobile phase, flow rate of 1 mL/min, column temperature of 40 °C, and detection wavelength of 278 nm.
  • encapsulation rate encapsulated drug amount/total content of main drug ⁇ 100%
  • Example 1 No shrinkage, no collapse good 91 12.37
  • Example 2 No shrinkage, no collapse good 85 17.6
  • Example 3 No shrinkage, no collapse good 87 18.5
  • Example 4 No shrinkage, no collapse good 88 18.9
  • Example 5 No shrinkage, no collapse good 86 18.6
  • Example 6 No shrinkage, no collapse good 87 28.1
  • Example 7 No shrinkage, no collapse good 85 25.3
  • Example 8 No shrinkage, no collapse good 84 29.4
  • Example 9 No shrinkage, no collapse good 87 31.3
  • Example 10 No shrinkage, no collapse good 88 27.5
  • HCT116 cells were used for cytotoxicity experiments. HCT116 cells were seeded in a 96-well plate/5% CO 2 /37°C incubator at an inoculum of 1 ⁇ 10 4 cells/well for 24 hours, and the concentrations were given respectively.
  • the rapamycin nano-release agent significantly inhibited HCT116
  • the growth of the cells is shown in Figure 3.
  • the IC 50 for 24 hours of administration is 10.29 ⁇ g/mL
  • the IC 50 for 48 hours of administration is 3.92 ⁇ g/mL
  • the IC 50 for 72 hours of administration is 0.63 ⁇ g/mL.
  • Modeling of HCT116 solid tumor mice Take 20 BALB/c nude mice, females, weighing 20 g, and inoculate 0.2 mL subcutaneously with the prepared HCT116 cell suspension, the number of cells is 5 ⁇ 10 6 .
  • Group administration After vaccination, they were randomly divided into five groups. The dosage of rapamycin nano sustained-release agent was 13.3 ⁇ g, 40 ⁇ g and 120 ⁇ g groups, namely low, medium and high dose groups, and a rapamycin control group of 40 ⁇ g and Normal saline control group. Four animals in each group were administered by tail vein injection with a 0.2 mL administration volume on the fifth day after vaccination, once every two days (approximately 56 hours), for 21 consecutive days.
  • Example 4 The rapamycin in Example 4 was replaced with DiR liposomes to make a nano-released DiR liposome.
  • As a control group after the tail vein was injected into nude mice, live imaging was performed at different time points to observe the position of fluorescence . It was found that after 18 hours, the nanoparticles gathered at the tumor site. The results are shown in Figure 4, 4D and 4E.
  • Figure 4D shows the targeting effect of the DiR liposome nano-release agent on tumor tissues at different time points;
  • Figure 4E shows the fluorescence results of the internal organs and tumor tissues taken out by the DiR liposome nano-release agent for 24 hours.
  • the sustained-release agent of the present application can make the effective ingredients reach the tumor directly, has a long-lasting action time, and has a better targeting effect.
  • HCT116 solid tumor mouse model Take 20 BALB/c nude mice, female, weight (20) g, and subcutaneously inoculate 0.2 mL of the mouse with the prepared HCT116 cell suspension, the cell number is 5 ⁇ 10 6 A.
  • Grouped administration Randomly divided into five groups after inoculation.
  • the rapamycin nano sustained-release agent in Example 4 is 13.3 ⁇ g, 40 ⁇ g, and 120 ⁇ g groups, namely low, medium and high dose groups, and a rapamycin control group 40 ⁇ g And the normal saline control group.
  • Four animals in each group were administered by tail vein injection with a 0.2 mL administration volume on the fifth day after vaccination, once every two days (approximately 56 hours). The administration was continued for 21 days.
  • Tumor volume was measured every other day after administration. 50 hours after the last administration, the mice were weighed, the mice were sacrificed, the tumors were taken, the tumors were weighed, and the tumor inhibition rate of each group was calculated.
  • Figure 5A is the dosage regimen for nude mice;
  • Figure 5B is the tumor volume after the administration of rapamycin nano-released agent;
  • Figure 5C is the tumor weight after the administration of rapamycin nano-released agent. It can be seen from the above figure that, compared with the direct administration of ordinary rapamycin, the nano sustained-release agent of the present application can significantly inhibit the growth of tumors.

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Abstract

Est divulgué un agent à libération prolongée à l'échelle nanométrique de rapamycine, préparé à partir des matières premières suivantes, en parties en poids : 1 partie de rapamycine, 0,5 à 20 parties de support polymère soluble, 40 à 200 parties de solvant organique et 400 à 20 000 parties de phase aqueuse. L'agent à libération prolongée à l'échelle nanométrique de rapamycine a une structure de nanomicelle et une taille de particule de 10 à 200 nm. L'agent à libération prolongée à l'échelle nanométrique de rapamycine présente un faible risque pour les vaisseaux sanguins. La demi-vie de l'agent à libération prolongée de rapamycine dans le sang peut aller jusqu'à 50 heures ou plus. L'agent à libération prolongée à l'échelle nanométrique de rapamycine peut directement atteindre la zone affectée par une tumeur. Avec un traitement continu, le taux de régression tumorale peut atteindre 50 %.
PCT/CN2020/082852 2019-09-26 2020-04-01 Agent à libération prolongée à l'échelle nanométrique de rapamycine et son procédé de préparation WO2021057007A1 (fr)

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