WO2018108164A1 - Composition pharmaceutique de bortézomib et ses applications - Google Patents

Composition pharmaceutique de bortézomib et ses applications Download PDF

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WO2018108164A1
WO2018108164A1 PCT/CN2017/116587 CN2017116587W WO2018108164A1 WO 2018108164 A1 WO2018108164 A1 WO 2018108164A1 CN 2017116587 W CN2017116587 W CN 2017116587W WO 2018108164 A1 WO2018108164 A1 WO 2018108164A1
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weight
parts
bortezomib
acid
oil
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PCT/CN2017/116587
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English (en)
Chinese (zh)
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甘勇
朱全垒
朱春柳
季亮
金宇良
郭仕艳
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宁波宁融生物医药有限公司
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Priority to CN201780075214.7A priority Critical patent/CN110381975A/zh
Publication of WO2018108164A1 publication Critical patent/WO2018108164A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/05—Dipeptides
    • 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
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • 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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • 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
    • 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
    • A61K9/127—Liposomes
    • 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
    • A61K9/127—Liposomes
    • A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
    • 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
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • 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
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to the field of pharmaceutical preparations and biology, and in particular to a bortezomib pharmaceutical composition and its use for treating cancers such as multiple myeloma, which have controlled release behavior and can maintain stability In vivo plasma concentration and long-acting proteasome inhibitory activity.
  • Bortezomib has the molecular formula of C 19 H 25 BN 4 O 4 and has a molecular weight of 384.237. Its chemical name is: [(1R)-3-methyl-1-[[(2S)-1-oxo-3-phenyl) -2-[(Pyrazinecarboxy)amino]propyl]amino]butyl]boronic acid having the following chemical structure:
  • the nuclear factor-KB (NF-KB) function of the cell promotes protein family initiation or promotes nuclear signaling, but is retained in the cytoplasm by a specific inhibitor NF-KB inhibitor (IKB) in normal cells. It is inactive. When IKB is phosphorylated, the ubiquitination of IKB is triggered, and the 26S proteasome causes rapid degradation of IKB. When IKB is degraded by the proteasome, NF-KB is transferred to the nucleus.
  • the 26S proteasome is the major protein degradation pathway in the cell, which is present in the cytoplasm and nucleus of all eukaryotic cells. It consists of a 20S core particle and two 19S cap structures.
  • the 20S core particles have a cylindrical shape, consisting of two ⁇ -rings in the inner layer and two ⁇ -rings in the outer layer.
  • the ⁇ -subunit is mainly used for substrate recognition, and the ⁇ -subunit is mainly involved in substrate degradation.
  • the proteasome inhibitor bortezomib, binds directly to the active site of the 20S core, reversibly inhibits 26S proteasome activity, causes IKB aggregation, prevents the release of NF-KB, and reverses the activation of NF-KB to inhibit tumors.
  • the proteasome inhibitor bortezomib
  • binds directly to the active site of the 20S core reversibly inhibits 26S proteasome activity, causes IKB aggregation, prevents the release of NF-KB, and reverses the activation of NF-KB to inhibit tumors.
  • IKB nuclear transcription factor NF-KB and its inhibitory unit IKB
  • tumor suppressor gene p53 tumor suppressor gene p53
  • cyclin-dependent kinase inhibitor protein cyclin-dependent kinase inhibitor protein and various pro-apoptotic proteins.
  • a disorder occurs, which activates multiple apoptotic pathways and induces MM cell apoptosis.
  • Blocking NF-KB leads to a decrease in the expression of myeloma cell adhesion factor, which interferes with the production of interleukin-6 by bone marrow stromal cells mediated by adhesion factors.
  • Bortezomib can also interfere with the mitogen-activated protein kinase p44/42 pathway associated with proliferative signaling, inducing accumulation of the cell cycle-dependent kinase inhibitors p21 and p27, when cell cycle-dependent kinase function When inhibited, cells cannot enter the S phase from the G1 phase, resulting in cell death.
  • malignant cell lines are 100 to 1000 times more sensitive to proteasome inhibition than non-malignant cell lines. When the proteasome activity is inhibited, normal cells are in a protected state in the G0 phase, and the tumor cells are still in the cell cycle, so bortezomib has a selective killing effect on MM cells.
  • Bortezomib (trade name: Valcade) is an injectable drug for multiple myeloma approved by the FDA in 2003. It can be administered intravenously or subcutaneously. The recommended dose of this product is single. 1.3 mg/m 2 was injected twice a week for 2 weeks (ie, on days 1, 4, 8 and 11) after 10 days of discontinuation (ie from day 12 to day 21). 3 weeks is a course of treatment, and the two doses are at least 72 hours apart. In clinical studies, patients who were confirmed to have complete remission received another 2 cycles of treatment, and patients who were advised to relapse received 8 cycles of treatment.
  • bortezomib was developed into a sustained-release preparation to maintain a blood concentration greater than the onset concentration of 2 ng/ml within 11 days, followed by withdrawal for 10 days to restore its protein activity.
  • the patient can achieve the therapeutic effect for a long time after administration once, reduce the toxicity caused by C max , improve the compliance of the patient, and reduce the cost of medication. Therefore, it is more feasible to develop bortezomib into a sustained-release preparation;
  • the object of the present invention is to develop a bortezomib pharmaceutical composition, which can control the absorption rate and absorption time of bortezomib in vivo by controlling the release behavior, thereby controlling the blood concentration in the body.
  • the level and its fluctuation range maintain the long-term homeostasis of the blood drug concentration in the body to the effective proteasome inhibition level, improve the anti-tumor effect of bortezomib, and reduce the adverse reactions after administration.
  • the formulation patents related to bortezomib include: 1) ordinary immediate release preparations for injection of bortezomib, such as bortezomib solution preparation (WO2016001905), liposome for injection (CN200580045755.2, CN 101795671) ), lyophilized powder preparation (CN 104586776A, CN102784114A, CN 105496960); 2) controlled release preparation, such as: controlled release preparation combined with topological enzyme (CN101336893A), can be seen from the patent search results, there is no relevant bortezomib A related study on single-use long-acting slow-release preparations.
  • bortezomib solution preparation WO2016001905
  • liposome for injection CN200580045755.2, CN 101795671
  • lyophilized powder preparation CN 104586776A, CN102784114A, CN 105496960
  • controlled release preparation such as: controlled release preparation combined with topological enzyme (
  • the present invention discloses a controlled release composition capable of precisely regulating the concentration level and fluctuation range of bortezomib blood, which composition can controllably adjust the blood concentration required for proteasome inhibition.
  • the primary object of the present invention is to provide a bortezomib pharmaceutical composition with controlled in vivo absorption behavior, blood concentration and proteasome inhibition level, in view of the biological properties of bortezomib and the efficacy and safety requirements of clinical treatment.
  • the present invention relates to a combination of novel drugs with improved bortezomib drug loading and/or in vivo absorption and/or bioavailability and/or blood drug concentration control and/or enzyme inhibition level control and their use as sole formulations or with other therapies The use of combination therapy for cancer.
  • the bortezomib active ingredient in the bortezomib pharmaceutical composition provided by the present invention may be in the form of a free base of bortezomib or a compound in the form of a pharmacologically acceptable salt thereof. Therefore, the active ingredient bortezomib in the pharmaceutical composition of the present invention includes the free base of bortezomib and a pharmacologically acceptable salt thereof.
  • the present invention provides a bortezomib pharmaceutical composition
  • a bortezomib pharmaceutical composition comprising 0.1 to 200 parts by weight, preferably 0.5 to 200 parts by weight, of the active ingredient bortezomib, 0.1 to 500 parts by weight, preferably 0.5 to 500 parts by weight Excipient for release rate adjustment; 0-1000 parts by weight, preferably 0.1-300 parts by weight, more preferably 0.1-100 parts by weight, more preferably 0.1-10 parts by weight of small molecule regulator; 0-2000 parts by weight, preferably 0.1-2000 Parts by weight of pharmaceutically acceptable injectable solvents.
  • the release rate adjusting excipient is selected from the group consisting of pharmaceutically acceptable excipients capable of achieving a local injection sustained release effect, preferably selected from the group consisting of pharmaceutically biodegradable reservoir type controlled release materials, medicinal oils and fats, pharmaceutically active surfactants, and the like.
  • the pharmaceutically biodegradable reservoir type controlled release material is selected from the group consisting of: sucrose acetate isobutyrate (SAIB), polylactic acid (PLA), polylactic acid-glycolic acid copolymer (PLGA), PEGylated PLA/PLGA, PLGA-PEG-PLGA copolymer, polyorthoesters, polyphosphate copolymer, fatty acid glyceride, triethylene glycol poly(orthoester) polymer, chitosan, water-soluble carboxymethyl Chitosan, fibroin, poly- ⁇ -hydroxybutyrate valerate, polylactide/lactide-polyethylene glycol copolymer and/or blend thereof, polycaprolactone-polyethylene glycol a combination of one or more of a copolymer, a poly- ⁇ -hydroxybutyrate and a polyethylene glycol blend and a polylactic acid/glycolic acid blend; the pharmaceutically acceptable sur
  • the small molecule regulator is selected from the group consisting of: acetic acid, anhydrous citric acid, ascorbic acid, calcium chloride, cresol, calcium disodium edetate, sodium edetate, glycine, histidine, lysine Acid, hydrochloric acid, lactic acid, lactose monohydrate, magnesium chloride, mannitol, methanesulfonic acid, methionine, phenol, phosphoric acid, anhydrous dipotassium hydrogen phosphate, sodium acetate, sodium ascorbate, sodium hydrogencarbonate, sodium hydrogen sulfite, sodium chloride , sodium citrate, sodium hydroxide, sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, sodium carbonate, sodium hydrogencarbonate, meglumine, protamine, One or more of propylparaben, cholesterol, phytosterol, arginine, triethanolamine
  • the pharmaceutically acceptable injectable solvent is water, benzyl alcohol, chlorobutanol, dimethyl sulfoxide, methyl pyrrolidone, dimethyl acetamide, propylene glycol, polyethylene glycol, polyethylene glycol (mono) methyl ether, three One or a combination of two or more of glycerin acetate, benzyl benzoate, glycerol aldehyde, glycerol formal, propylene glycol, ethanol, ethylene glycol diethyl ether.
  • the pharmaceutical composition provided by the present invention may be in the form of a solution, a suspension, a lyophilized powder or a syringe filled with a drug powder or a solution for injection or implantation in a subcutaneous, intradermal, muscle or the like.
  • the pharmaceutical composition provided by the present invention may be selected from suspensions for local injection or implantation, oil needle preparations, sustained release microspheres, implanted gels, multivesicular liposomes and other applicable reservoirs.
  • Type controlled release local injection preparations such as SABER delivery system and Camurus FluidCrystal injection system, etc.).
  • the content of the pharmaceutically active ingredient (the amount contained in a single injection preparation) in the unit preparation before injection in the pharmaceutical composition provided by the present invention is about 0.1 to 200 mg, preferably the preparation contains a dose of 0.5 to 100 mg, more preferably 1 to 50 mg. Even more preferably 1-20 mg, the volume of a single local injection or burying required on the human body is 0.5-2 mL, preferably less than 1 mL per injection or implant.
  • the bortezomib pharmaceutical composition provided by the invention has a controlled release behavior, and after release by injection or implantation, the release behavior and release amount can be released in a release medium meeting the sump condition within a predetermined period of time.
  • Control in the aqueous medium, at 37 ° C, the release amount within 1 hour is less than 20% of the total amount of bortezomib, preferably less than 10%, or even less than 5%; 24h release is less than 40% of the total amount of bortezomib Preferably, less than 30%, even less than 20%; 90% drug release time > 3 days, even greater than 7 days, greater than 10 days or greater than 15 days.
  • the pharmaceutical composition provided by the invention can quickly achieve the blood concentration level required for effective anti-tumor proteasome inhibition after injection, and can avoid fluctuation of blood concentration and maintain effective Blood concentration is a few days, even ten days.
  • the effective blood drug concentration can be maintained in the range of 1-200 ng/mL for several days to ten days, even the plasma concentration is maintained at 1.5-100 ng/mL, and even the plasma concentration is maintained at 2-50 ng/mL.
  • the decrease of blood concentration fluctuation and the long-term and high-efficiency proteasome inhibition effect are expected to improve the anti-tumor effect and reduce the generation of toxicity, and achieve the regulation of the more efficient and low-toxicity of tumor patients and the regulation of the frequency of administration.
  • the present invention provides the use of the bortezomib pharmaceutical composition for the preparation of a medicament for the treatment and/or prevention of cancers such as multiple myeloma.
  • the bortezomib pharmaceutical composition provided by the invention can be used for clinical treatment of cancers such as multiple myeloma.
  • Controllable release and absorption of the drug can be achieved, providing accurate in vivo blood concentration and long-term stable proteasome inhibition level, and lasting effect;
  • the safety window is large.
  • the clinical dose and dosage regimen can be flexibly adjusted, which is expected to further increase the therapeutic dose and enhance the anti-tumor effect.
  • Figure 1 shows the in vitro release profile of the bortezomib in situ precipitated gel formulation of Example 1.
  • Figure 2 shows the in vitro release profile of the bortezomib sustained release microspheres of Example 2.
  • Figure 3 shows the in vitro release profile of the bortezomib polycapsule liposomes of Example 4.
  • Figure 4 shows the in vitro release profile of the bortezomib in situ temperature sensitive gel formulation of Example 6.
  • Figure 5 is a graph showing the canine drug time of the immediate release bortezomib formulation of Comparative Example 1 and the bortezomib in situ gel reservoir type injection of Example 1.
  • the polycapsules (Liposomes) provided by the present invention are mainly microcapsules composed of cholesterol and phospholipids and similar to the biofilm bilayer structure, and are novel drug carriers.
  • Liposomes can be divided into three categories according to their structure: single-chamber liposome (ULV), multi-chamber liposome (MLV), and multivesicular liposome (MVL), of which the first two are concentric liposomes, while MVL It belongs to non-concentric liposome.
  • MVL is an aggregate formed by non-concentric lipid bilayer vesicles. It is a new type of liposome that delivers drugs.
  • the injection enters the body to form a drug reservoir, which produces a good sustained release effect, which not only reduces the number of times of administration of the patient, but also improves the compliance of the treatment, and has become a research hotspot of many scholars.
  • the bortezomib pharmaceutical composition of the present invention may be in the form of a bortezomib multivesicular liposome, wherein the bortezomib multivesicular liposome composition comprises the active ingredient bortezomib, a lipid component (including fats and oils, and surface active) And a combination of one or more of the optional pharmaceutically acceptable pH/osmotic pressure adjusting agents; wherein the bortezomib multivesicular liposome composition comprises 0.1 to 200 parts by weight, preferably 0.5 100 parts by weight, more preferably 1 to 50 parts by weight, even more preferably 1 to 20 parts by weight of the active ingredient bortezomib, 0.1 to 300 parts by weight, preferably 0.1 to 200 parts by weight, of the lipid component, and optionally 0 to 1000 parts by weight, preferably 0.1 to 300 parts by weight, more preferably 0.1 to 100 parts by weight, still more preferably 0.1 to 10 parts by weight of the lipid film
  • the bortezomib is the only active ingredient loaded into the interior of the multivesicular liposome; the formulation composition may comprise free bortezomib not encapsulated by polycystic liposomes, free bortezol not loaded with polyvesicular liposomes
  • the amount of rice is generally less than 20%, preferably less than 10%, of the total amount of bortezomib in the composition.
  • the lipid component is at least one amphiphilic lipid and/or at least one neutral lipid; the amphiphilic lipid is one selected from the group consisting of phosphatidylcholine, phosphatidylglycerol, and a corresponding salt.
  • the phosphatidylglycerol can be DPPG, and in certain instances, the phosphatidylcholine can be DEPC or DOPC or a combination thereof;
  • the neutral lipid can be Selected from ethylene glycol esters, squalene, glycerin, triglycerides, and propylene glycol esters
  • the triglyceride may be selected from the group consisting of oleic acid triglyceride and caprylic acid triglyceride.
  • the composition preferably includes a lipid membrane fluidity modifier, an osmotic pressure regulator, or a pH adjuster;
  • the lipid membrane fluidity modifier can be selected from the group consisting of cholesterol, phytosterols, and the like; It is one or a combination of two or more selected from the group consisting of a non-organic acid, an organic acid, a non-organic base, and an organic base, and specifically, the pH adjuster is selected from the group consisting of hydrochloric acid, phosphoric acid, tartaric acid, histidine, lysine, and butyl.
  • the osmotic pressure adjusting agent is one or a combination of two or more selected from the group consisting of sodium chloride, glucose, sucrose, and mannitol;
  • the aqueous phase of the outer phase of the multivesicular liposome can range in pH from 4.0 to 9.0.
  • the single injection dose of the active ingredient bortezomib in the preparation of the multivesicular liposome composition ranges from 0.1 to 200 mg, and in some instances, the amount of uncoated free bortezomib accounts for total bortezomib in the composition. 0-10% of the amount.
  • the multivesicular liposome compositions provided by the present invention can be administered intravenously, subcutaneously or intramuscularly, preferably by subcutaneous injection.
  • the preparation method of the polycystic liposome of the present invention adopts a conventional method in the art, for example, a double emulsion method, specifically, the following five steps are required: (1) firstly dissolving a prescribed amount of the lipid component in the easy
  • the volatile organic solvent usually chloroform or a mixture of chloroform and diethyl ether
  • forms an oil phase and the prescribed amount of bortezomib is dissolved in water to form a medicated aqueous solution (first aqueous phase), and then in a suitable oil-water volume ratio ( The volume ratio is 1:10-12:10, v/v)
  • the aqueous solution containing the drug (the first aqueous phase) is mixed with the organic phase of the lipid (oil phase) and prepared by ultrasonic or mechanical shearing at room temperature for a certain period of time.
  • Uniform water-in-oil (W/O) colostrum (2) Draw the formed W/O colostrum and inject a second aqueous buffer at a certain ratio (volume ratio 1:10-5:10, v /v), mechanically sheared again at 30 ° C to form a stable water-in-oil-in-water (W / O / W) type of double emulsion; (3) transfer the double emulsion into the Erlenmeyer flask, with an inert gas ( If the organic solvent (ether, chloroform, dichloromethane, etc.) in the double emulsion is removed, such as nitrogen, the nitrogen solvent may be introduced into the surface or the nitrogen conduit may be inserted into the bottom of the conical flask to remove the organic solvent; (4) , The available and suitable for storing a physiologically acceptable salt solution (e.g., 0.9% sodium chloride solution) substitution second aqueous phase concentrated; (5) adjusting the content of the drug, depending on the content filling.
  • the lipids used generally include neutral lipids (commonly used triglycerides), phospholipids, and cholesterol.
  • Neutral lipids are an important part of the MVL preparation process, otherwise ordinary liposomes can only be obtained.
  • the methods for preparing colostrum include: ultrasonic, high-speed dispersion, emulsion homogenizer, nozzle atomization, etc., and vortex mixer or high-speed disperser is often used in the laboratory for emulsification.
  • Different types of media and lipids encapsulated in the prescription will cause different release rates of the drug, and the different carbon chain length of the neutral lipid triglyceride can regulate the release rate of the drug.
  • the time, temperature, speed, volume of the outer aqueous phase, nitrogen flow rate, and method of separating the free drug during the preparation of MVL also have an effect on the particle size, encapsulation efficiency, encapsulation volume and stability.
  • the bortezomib polycapsule liposomes with different release rates can be obtained by adjusting the above process conditions.
  • the polycystic liposome provided by the invention has a release amount less than 20%, preferably less than 10%, or even less than 5% of the total amount of bortezomib in the preparation within 6 hours; and the release amount of 24h is less than 40% of the total amount of bortezomib %, preferably less than 30%, even less than 20%; 90% drug release time > 3 days.
  • the pharmaceutical composition provided by the invention can quickly reach the blood drug concentration level required for effective anti-tumor proteasome inhibition after injection, and can avoid fluctuation of blood drug concentration, maintain the effective blood drug concentration for several days, or even Dozens of days.
  • the effective blood drug concentration can be maintained in the range of 1-200 ng/mL for several days to several tens of days, and even the plasma concentration is greater than 1.5 ng/mL ⁇ C ⁇ 100 ng/mL for more than 7 days.
  • the bortezomib pharmaceutical composition provided by the present invention can be practiced in the form of a bortezomib suspension to achieve the release behavior.
  • the suspension may be selected from aqueous vehicle suspensions or oily vehicle suspensions.
  • the bortezomib suspension comprises the active ingredient bortezomib, an excipient for release rate adjustment, a pharmaceutically acceptable injectable solvent, and/or a suspension stabilizer, and/or an isotonicity agent, a buffering agent, and the like;
  • the bortezomib suspension comprises 0.1-200 parts by weight, preferably 0.5-100 parts by weight, more preferably 1-50 parts by weight, even more preferably 1-20 parts by weight of the active ingredient bortezomib; 0- 2000 parts by weight, preferably 0 to 300 parts by weight, more preferably 0.5 to 300 parts by weight of the pharmaceutically acceptable injectable solvent; 0.1 to 500 parts by weight, preferably 0.5 to 500 parts by weight, of the release rate adjusting auxiliary; 0 to 1000 parts by weight, It is preferably 0.1 to 300 parts by weight, more preferably 0.1 to 100 parts by weight, still more preferably 0.1 to 5 parts by weight, of the isotonic agent and/or buffer.
  • the release rate adjusting excipient may be selected from the group consisting of medicinal oils, surfactants, or polymers.
  • the medicinal oils and fats may include coconut oil, castor oil, sesame oil, corn oil, soybean oil, peanut oil, cottonseed.
  • the surfactant may include phospholipid for injection, polysorbate 80, polysorbate 20, polyoxyethylene castor oil 50, polyoxyethylene One or a combination of castor oil 60, poloxamer and polyoxyethylene fatty acid ester, the polymer may be selected from the group consisting of sodium carboxymethyl cellulose, vinyl acetate copolymer, poloxamer, poly One or a combination of two or more of ethylene glycol, hydroxylactic acid polymer, polyester, polypolysaccharide, and povidone K12/K17.
  • the pharmaceutically injectable solvent is selected from the group consisting of water, benzyl alcohol, chlorobutanol, dimethyl sulfoxide, methyl pyrrolidone, dimethyl acetamide, propylene glycol, polyethylene glycol, polyethylene glycol (single)
  • the buffer may be selected from the group consisting of sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium citrate, potassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, sodium carbonate, sodium hydrogencarbonate, meglumine, and refined ammonia.
  • the isotonic agent may be selected from one or a combination of two or more of sodium chloride, sucrose, glucose, and mannitol.
  • the suspension provided by the present invention may be a nanosuspension or a microsuspension, the nanosuspension has a particle size ranging from 50 to 800 nm, and the microsuspension has a particle size ranging from 1 to 18 ⁇ m.
  • It can be prepared by a homogenization destruction method or the like which is common in the art, such as first dissolving the suspension stabilizer in water, and placing the active drug in the above solution containing the stabilizer, after preliminary shearing and crushing, at a certain temperature, The cycle is homogenized and crushed to obtain a suspension having a uniform particle size.
  • the single dose of the active ingredient bortezomib in the suspension provided by the present invention is in the range of 0.1-200 mg, preferably 0.5-100 mg; the bortezomib suspension provided by the present invention can be administered subcutaneously or intramuscularly, preferably Subcutaneous injection.
  • In situ gel preparation is a kind of reservoir-type local injection preparation, and it is a research hotspot in the field of slow-controlled injection in recent years. It is to dissolve drugs and polymers in a suitable solvent, local subcutaneous injection, and administration. At the site, the polymer solidifies under physiological conditions to form a semi-solid or solid drug depot.
  • In situ gel overcomes the shortcomings of common emulsions, liposomes, microspheres and micelles, has local application for lesions, prolongs the release period, reduces the dosage and adverse drug reactions, and avoids the implantation of implants. The pain during implantation and the relatively simple process.
  • the bortezomib pharmaceutical composition provided by the present invention can achieve the release behavior by the form of a bortezomib in situ gel system, characterized in that the in situ gel system comprises the active ingredient drug bortezomib, a suitable solvent, The release rate adjusting gel forming material.
  • the bortezomib in situ gel system comprises 0.1 to 200 parts by weight, preferably 0.5 to 100 parts by weight, even more preferably 1 to 50 parts by weight, even more preferably 1 to 20 parts by weight of the active ingredient bortezomib; - 2000 parts by weight, preferably 50 to 2000 parts by weight, more preferably 100 to 1000 parts by weight, of a pharmaceutically acceptable injectable solvent; 0.1 to 500 parts by weight, preferably 0.5 to 250 parts by weight, even more preferably 1 to 100 parts by weight
  • the release rate adjusting gel forming material 0.1 to 200 parts by weight, preferably 0.5 to 100 parts by weight, even more preferably 1 to 50 parts by weight, even more preferably 1 to 20 parts by weight of the active ingredient bortezomib; - 2000 parts by weight, preferably 50 to 2000 parts by weight, more preferably 100 to 1000 parts by weight, of a pharmaceutically acceptable injectable solvent; 0.1 to 500 parts by weight, preferably 0.5 to 250 parts by weight, even more preferably 1 to 100
  • the bortezomib in situ gel system can be prepared in a manner well known in the art.
  • the pharmaceutically acceptable polymer polylactic acid or polylactic acid-glycolic acid can be dissolved in a solvent such as polyethylene glycol methyl ether or N-methylpyrrolidone.
  • the gel-forming material for adjusting the release rate of the copolymer and the like forms a solution which can directly dissolve the active drug bortezomib or pre-filled with the active drug in a sterile syringe, and then dissolve the drug before use.
  • the solution after dissolving the drug is locally injected into the human body, and the solvent for dissolving the gel forming material is rapidly absorbed locally, and the partially dissolved drug is also rapidly absorbed by the absorption of the solvent, and the gel material is in a semi-solid or solid state in the aqueous environment.
  • the gel while most of the active drug dissolved or dispersed into the gel system is slowly released as the gel degrades and dissolves, achieving smooth absorption of the drug in the body and maintenance of blood concentration.
  • Suitable solvents in the in situ gel system of the present invention may be selected from the group consisting of water, N-methylpyrrolidone, polyethylene glycol (mono) methyl ether, triacetin, benzyl benzoate, glycerol aldehyde And one or a combination of two or more of glycerol formal, propylene glycol, ethanol, ethylene glycol diethyl ether, benzyl alcohol, and dimethyl sulfoxide.
  • the gel forming material for release rate adjustment comprises: polylactic acid (PLA), polylactic acid-glycolic acid copolymer (PLGA), polyorthoester, sucrose acetate isobutyrate, PLGA-PEG-PLGA copolymer, fatty acid Glyceride, One or a combination of two or more of pegylated PLA/PLGA, polycaprolactone-polyethylene glycol copolymer, triethylene glycol poly(orthoester) polymer, poloxamer.
  • PLA polylactic acid
  • PLGA polylactic acid-glycolic acid copolymer
  • polyorthoester sucrose acetate isobutyrate
  • PLGA-PEG-PLGA copolymer sucrose acetate isobutyrate
  • PLGA-PEG-PLGA copolymer sucrose acetate isobutyrate
  • PLGA-PEG-PLGA copolymer sucrose acetate isobutyrate
  • the single dose of the active ingredient bortezomib in the in situ gel system ranges from 0.1 to 200 mg, preferably from 0.5 to 100 mg, more preferably from 1 to 50 mg, even more preferably from 1 to 20 mg.
  • the bortezomib in situ gel system provided by this method has a release amount of less than 20% or even less than 10% of the total amount of bortezomib in the preparation within 6 hours; the release amount of 24h is less than 40% of the total amount of bortezomib. Even less than 30%; 90% drug release time > 3 days.
  • the botinzomib in situ gel system provided by the invention can rapidly achieve the blood drug concentration level required for effective anti-tumor proteasome inhibition, and can avoid the fluctuation of blood concentration and maintain the effective blood concentration. A few days, even dozens of days.
  • the effective blood drug concentration can be maintained in the range of 1-200 ng/mL for several days to several tens of days, and even the plasma concentration is greater than 1.5 ng/mL ⁇ C ⁇ 100 ng/mL for more than 7 days.
  • the in situ gel system provided by the present invention can be stored in a short-term solution state or in the form of a syringe pre-packaged with a drug and a solvent.
  • the in situ gel system provided by the present invention can be administered intravenously, subcutaneously or intramuscularly, preferably subcutaneously and intramuscularly.
  • the microsphere provided by the present invention refers to a microscopic spherical entity formed by dissolving or dispersing a drug in a matrix of a sustained-release polymer material, and having a small particle size and belonging to a matrix-type skeleton particle.
  • Microspheres have the advantages of high efficiency, non-toxicity, constant drug release rate and controllable particle size, and have been widely used in the development of long-acting injections.
  • the rate of drug release from microsphere injections is primarily determined by the polymer delivery system.
  • the microspheres When the microspheres are injected into the subcutaneous or intramuscular, the drug can be slowly released from the microsphere matrix, and the skeleton material can be gradually hydrolyzed and dissolved.
  • the final product of the degradation is CO 2 and water, which is easily absorbed by the body without causing adverse reactions.
  • the release behavior drug composition of the present invention can be provided in the form of bortezomib microspheres comprising the active ingredient bortezomib and a release rate adjusting polymer material.
  • the sustained release microsphere of the present invention comprises 0.1 to 200 parts by weight, preferably 0.5 to 100 parts by weight, even more preferably 1 to 50 parts by weight, even more preferably 1 to 20 parts by weight of the active drug bortezomib, and 0.1 to 500 parts by weight.
  • the fraction preferably from 0.2 to 250 parts by weight, even more preferably from 1 to 200 parts by weight, of the release rate adjusting polymer.
  • the microsphere preparation provided by the invention is a dry powder, and is sprayed uniformly with water for injection or other solvent before use; the other solvent is an injection solvent which does not affect the stability of the microsphere, and is preferably selected from the group consisting of polyethylene glycol.
  • the other solvent is an injection solvent which does not affect the stability of the microsphere, and is preferably selected from the group consisting of polyethylene glycol.
  • the bortezomib sustained-release microspheres can be prepared by a method known in the art. Specifically, the active drug bortezomib and the release rate adjusting polymer material can be dissolved in a suitable solvent to intelligently spray dry static electricity.
  • the collection system is spray dried to collect and prepare; bortezomib and a suitable release-regulating polymer material such as polylactic acid-glycolic acid copolymer (PLGA) are first dissolved in a solvent such as dichloromethane at a rate of 0.2-1 ml/min.
  • a suitable solvent such as dichloromethane
  • drying temperature is about 40 °C-80 °C, in the spray drying process, real-time monitoring of microsphere size, adjusting injection rate, spray frequency, heating Temperature and ventilation volume, after the end of spray drying, collect the microsphere powder on the wall of the electrostatic collection system, the concentration of the drug and polymer solution, the injection rate of the system, the spray frequency, the drying temperature and the ventilation volume, etc.
  • the physicochemical properties and yield of the ball have a great influence.
  • a sustained-release microsphere preparation having a uniform particle diameter can be obtained, and the particle size of the sustained-release microsphere provided by the present invention is generally between 0.5 and 20 ⁇ m.
  • the sustained-release microspheres provided by the invention are locally injected into the human body, and the drug is slowly released due to degradation and dissolution of the polymer matrix for release rate regulation, thereby achieving stable absorption of the drug and maintenance of blood drug concentration in the body.
  • the polymer matrix material for release rate adjustment comprises: polylactic acid (PLA), polylactic acid-glycolic acid copolymer (PLGA), pegylated PLA/PLGA, chitosan, water-soluble carboxymethyl chitosan , fibroin, poly- ⁇ -hydroxybutyrate valerate, polylactide/lactide-polyethylene glycol copolymer blend, poly- ⁇ -hydroxybutyrate and polyethylene glycol blend, One or a combination of two or more of a polylactic acid/glycolic acid blend and a pharmaceutically acceptable topical injection controlled release material.
  • PLA polylactic acid
  • PLGA polylactic acid-glycolic acid copolymer
  • pegylated PLA/PLGA pegylated PLA/PLGA
  • chitosan water-soluble carboxymethyl chitosan
  • fibroin poly- ⁇ -hydroxybutyrate valerate
  • polylactide/lactide-polyethylene glycol copolymer blend poly- ⁇ -hydroxy
  • the microsphere system provided by the present invention can be stored for a long period of time in the form of a solid powder.
  • the sustained release microsphere preparation provided by the present invention can be administered intravenously, subcutaneously or intramuscularly, preferably subcutaneously and intramuscularly.
  • the bortezomib pharmaceutical composition provided by the present invention can be practiced in the form of a bortezomib oil needle formulation to achieve the release behavior described.
  • the bortezomib oil needle preparation comprises the active ingredient bortezomib, a release rate adjusting adjuvant and/or a pharmaceutically injectable solvent, and/or a small molecule regulator;
  • the bortezomib oil needle preparation comprises 0.1-200 parts by weight, preferably 0.5-100 parts by weight, more preferably 1-50 parts by weight, even more preferably 1-20 parts by weight of the active ingredient bortezomib 0.1-500 weight Parts, preferably 0.5 to 500 parts by weight of an excipient for release rate adjustment; 0 to 300 parts by weight, preferably 0 to 100 parts by weight, more preferably 0.1 to 100 parts by weight of a pharmaceutically acceptable injectable solvent; 0 to 1000 parts by weight, preferably 0.1 - 300 parts by weight, more preferably 0.1 to 100 parts by weight, still more preferably 0.1 to 10 parts by weight, of a small molecule regulator.
  • the release rate adjusting excipient is selected from the group consisting of medicinal oils, surfactants, or polymers.
  • the surfactant is selected from the group consisting of phospholipids for injection, polysorbate 80, and polysorbate.
  • the medicinal oil and fat used is selected from the group consisting of glycerin and cholesterol , propylene glycol ester, ethylene glycol ester, squalene, stearic acid, triglyceride (such as oleic acid triglyceride or caprylic triglyceride), glycerol oleic acid or a mixture thereof with phospholipids and one of the corresponding salts Or a combination of two or more;
  • the polymer is selected from the group consisting of sodium carboxymethyl cellulose, vinyl acetate copolymer, poloxamer, polyethylene glycol, hydroxylactic acid polymer, polyester, polypolysaccharide and polydimensional One of ketone K12/K17 or a combination of two or more;
  • the pharmaceutically injectable solvent may be selected from the group consisting of benzyl alcohol, chlorobutanol, dimethyl sulfoxide, methyl pyrrolidone, dimethyl acetamide, propylene glycol, polyethylene glycol, polyethylene glycol (mono) methyl ether, three One or a combination of two or more of glyceryl acetate, benzyl benzoate, ethyl oleate, glycerol aldehyde, glycerol formal, propylene glycol, ethanol, ethylene glycol diethyl ether;
  • the small molecule regulator is selected from the group consisting of sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium citrate, potassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, sodium carbonate, sodium hydrogencarbonate, meglumine, One or a combination of two or more of arginine, triethanolamine, citric acid, sodium chloride, glucose, sucrose, and mannitol.
  • the oil needle preparation provided by the invention can be prepared by a method commonly used in the art, such as first dissolving the active drug bortezomib in a pharmaceutically acceptable injectable solvent, adding the release regulating auxiliary material and the small molecule regulator evenly, or directly The active drug bortezomib, the release rate adjusting adjuvant and the small molecule regulator are dissolved in a pharmaceutically acceptable injectable solvent to prepare an oil needle preparation.
  • the single dose of the active ingredient bortezomib in the oil needle preparation provided by the invention ranges from 0.1 to 200 mg, preferably from 0.5 to 100 mg; the bortezomib oil needle preparation provided by the invention can be administered subcutaneously or intramuscularly, preferably Subcutaneous injection.
  • Experimental animals Beagle dogs are male and female, weighing 8-10 kg.
  • the source is Beijing Mars Biotechnology Co., Ltd.
  • the test animals were subjected to adaptive feeding at the test site of the Experimental Animal Center of Shanghai Pharmaceutical Research Institute 14 days before the test day.
  • a prescribed amount of pegylated PLA (having a molecular weight of 5000) was added to a vessel containing N-methylpyrrolidone, and stirred for 2 hours to give a uniform state, thereby obtaining a blank gel preparation; and then adding a prescribed amount of bortezole In the rice to blank gel preparation, stirring was carried out for 1 hour to obtain a homogeneous solution which was an in situ precipitated gel injection.
  • the obtained gel injection was poured into a vial containing distilled water, sealed and sealed, placed in a constant temperature water bath shaker (37 ° C, frequency 60 rpm, amplitude: 24 mm), respectively at the set time point, in the bottle All the solutions were taken out, and the same volume of the same distilled water medium was added and returned to the water bath shaker. After the removed release solution was centrifuged at 10,000 rpm for 5 min, 20 ⁇ l of the supernatant was accurately measured and injected into the liquid chromatograph. The chromatogram was recorded, the release percentage was calculated, and the release curve was drawn. The results are shown in Fig. 1.
  • the bortezomib and PLGA were dissolved in dichloromethane, and injected into the BUCHI B-290 with a drying temperature of 65 ° C, a spray frequency of 120 kHz, and a ventilation of 70 L/min at a sampling rate of 0.2 ml/min to 0.5 ml/min.
  • Example 2 The bortezomib microspheres of Example 2 were incubated in a release medium of physiological isotonic PBS solution (pH 7.4), and at 37 ° C, 100 r / min, at a predetermined time point, 5 ml of the eluate was taken, and centrifuged at 10,000 rpm for 5 min. Precisely take 20 ⁇ l of the supernatant into the liquid chromatograph, record the chromatogram, and make a cumulative drug release profile, as shown in Figure 2.
  • physiological isotonic PBS solution pH 7.4
  • Figure 2 shows that the sustained release microspheres release less than 20% of bortezomib in 1 hour, about 20% in 120 hours, and continue to release at 192 hours, with a cumulative release of less than 30%.
  • the preparation of the bortezomib suspension comprises the following steps: (1) adding the suspending agent sodium carboxymethylcellulose to an appropriate amount of water for injection, heating to 80 ° C, stirring, and bringing it into a uniform state to obtain a dispersion medium 1 (2) mixing the bortezomib starting material with the wetting agent polysorbate 20, adding water for injection to make a suspension; (3) slowly adding the suspension to the dispersion medium under stirring 1; (4) adding citric acid, sodium citrate, and adding appropriate Amount of water to a constant volume; (5) continuously stir the fixed volume of the suspension for 60-120 minutes to fully mix; (6) melt the mixed preparation into a sterilized and dried ampoule or The glass bottle is sealed to obtain a bortezomib suspension.
  • the preparation of bortezomib multivesicular liposome comprises the following steps: (1) firstly formulating a predetermined amount of cholesterol, dioleoylphosphatidylcholine (DOPC), dipalmitoylphosphatidylglycerol (DPPG), triolein Dissolved in an appropriate amount of chloroform-diethyl ether (1:1, v / v) solution as a lipid phase; (2) a predetermined amount of bortezomib, sucrose was dissolved in an appropriate amount of 60 mM hydrochloric acid solution, as an internal aqueous phase; (3) slowly adding the above internal aqueous phase to the upper layer of the lipid phase, stirring at a speed of 14000 rpm for 8 minutes with a high-speed shear homogenizer to obtain W/O type colostrum; (4) adding the above colostrum to the content of 5 mg/ml Glucose and 40mmol/L lysine in the external aque
  • the liposomes were isolated. The supernatant was discarded, and the precipitate was redispersed in an appropriate amount of physiological saline, and then precipitated by centrifugation. The cycle was repeated three times, and the precipitate was concentrated, and the precipitate was diluted with an appropriate amount of physiological saline to obtain a bortezomib vesicle liposome.
  • the bortezomib multicapsule liposome suspension of Example 4 was weighed, diluted with physiological saline, and the resulting suspension was placed in a 37 ° C constant temperature shaker (rotation speed of 100 rpm), and taken out at a predetermined time point. 3 ml sample, and add the same volume of physiological saline; centrifuge the sample at 10000 rpm for 5 min, accurately measure the supernatant 20 ⁇ l, inject into the liquid chromatograph, record the chromatogram, calculate the release percentage, and draw the release curve. The results are shown in Figure 3.
  • the bortezomib in situ temperature-sensitive gel was placed in a test tube, and a gel was formed at 37 ° C under a constant temperature oscillator. After 10 minutes, physiological saline was added, and then the tube containing the gel was placed in a constant temperature oscillator to control the temperature at 37.0 ° C ⁇ 0.5 ° C, the rotation speed is 100 rpm. The entire dissolution process seals the tube to prevent evaporation of water and affect the results of the experiment. Sampling at the set time point, the sample volume is 3mL, and 3mL constant temperature saline medium is added at the same time.
  • the released liquid is centrifuged at 10000rpm for 5min, then 20 ⁇ l of the supernatant is accurately taken, injected into the liquid chromatograph, and the chromatogram is recorded and calculated. The percentage was released and the release curve was plotted. The results are shown in Figure 4.
  • Bortezomib lyophilized powder injection (1) Weigh 200mg of bortezomib into a glass bottle containing tert-butanol, vortex and sonicate to fully dissolve to obtain solution 1; (2) Add 200mg of mannitol To 100 ml of water for injection, stir and dissolve, add 0.3% (w/v) needle with activated carbon, stir at 80 ° C for 10 min, remove carbon by filtration to obtain solution 2, and set aside; (3) mix solution 1 and solution 2, pass through micropores The filter membrane is sterilized, and water for injection is added to 200 ml; (4) the content is determined, filled, and lyophilized to obtain a lyophilized powder injection.
  • plasma concentration C max situ gel formulation provides reduced to 25ng / mL.
  • the in situ gel preparation can also quickly reach the blood concentration required for proteasome inhibition, and the blood concentration peak is significantly reduced, the maintenance time is significantly prolonged, and the long-term maintenance can be maintained.
  • the peak value of blood drug concentration is avoided, the toxicity side effect of the drug can be reduced, and at the same time, the enzyme inhibition effect and the anti-tumor effect are better exerted, and the drug dose climbing and the best drug effect are also exerted. Provides more space.

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Abstract

L'invention concerne une composition pharmaceutique de bortézomib et ses applications. La composition comprend les composants en parties en poids : de 0,1 à 200 parties de bortézomib, de 0,1 à 500 parties d'excipient de régulation de taux de libération, de 0 à 1000 parties de régulateur de micromolécule et de 0 à 2000 parties de solvant injectable. L'invention concerne également des applications de la composition pharmaceutique de bortézomib dans la préparation de médicaments utilisés pour le traitement du myélome multiple réfractaire/facilement récurrent.
PCT/CN2017/116587 2016-12-16 2017-12-15 Composition pharmaceutique de bortézomib et ses applications WO2018108164A1 (fr)

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CN115990134A (zh) * 2022-11-08 2023-04-21 四川大学华西医院 一种可注射水凝胶/纳米凝胶载药缓释体系及其制备方法和用途

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CN110063932A (zh) * 2019-04-12 2019-07-30 浙江大学 一种多肽蛋白类药物的缓释组合物制剂及其制备方法
WO2024067840A1 (fr) * 2022-09-30 2024-04-04 上海济煜医药科技有限公司 Liposome, procédé de préparation s'y rapportant et utilisation associée

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CN115990134A (zh) * 2022-11-08 2023-04-21 四川大学华西医院 一种可注射水凝胶/纳米凝胶载药缓释体系及其制备方法和用途
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