WO2018108164A1 - Bortezomib pharmaceutical composition and applications thereof - Google Patents

Bortezomib pharmaceutical composition and applications thereof Download PDF

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Publication number
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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French (fr)
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/en
Publication of WO2018108164A1 publication Critical patent/WO2018108164A1/en

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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.

Abstract

A bortezomib pharmaceutical composition and applications thereof. The composition comprises the components in parts by weight: 0.1 to 200 parts of bortezomib, 0.1 to 500 parts of release rate regulation excipient, 0 to 1000 parts of micromolecule regulator and 0 to 2000 parts of injectable solvent. Applications of the bortezomib pharmaceutical composition in the preparation of drugs used for treating refractory/easily-reoccurring multiple myeloma.

Description

一种硼替佐米药物组合物及其应用Bortezomib pharmaceutical composition and application thereof 技术领域Technical field
本发明涉及药物制剂领域和生物学领域，具体涉及一种硼替佐米药物组合物及其用于治疗多发性骨髓瘤等癌症的用途，所述药物组合物具有可控的释放行为，能够维持稳定的体内血药浓度和长效的蛋白酶体抑制活性。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.
背景技术Background technique
硼替佐米的分子式为C19H25BN4O4，分子量为384.237，其化学名称为：[(1R)-3-甲基-1-[[(2S)-1-氧-3-苯基-2-[(吡嗪羧基)氨基]丙基]氨基]丁基]硼酸，其具有下述化学结构：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:
Figure PCTCN2017116587-appb-000001
Figure PCTCN2017116587-appb-000001
细胞的核因子-KB(NF-KB)的功能是促进蛋白质家族启动或促进细胞核内的信号传导，但在正常的细胞内被特异性抑制物NF—KB抑制物(IKB)阻留在胞质而无活性。当IKB磷酸化后，引发了IKB的泛素化，进而26S蛋白酶体引起IKB的迅速降解，当IKB被蛋白酶体降解后，NF—KB转移到细胞核内发挥作用。26S蛋白酶体是细胞内主要的蛋白降解途径，存在于所有真核细胞的胞质和核内，它由1个20S核心颗粒和2个19S帽结构组成。20S核心颗粒呈筒状外形，由内层2个β环和外层2个α环组成，其中α亚基主要用于底物识别，β亚基主要参与底物降解。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 β-rings in the inner layer and two α-rings in the outer layer. The α-subunit is mainly used for substrate recognition, and the β-subunit is mainly involved in substrate degradation.
蛋白酶体抑制剂—硼替佐米可直接与20S核心部分的活性位点结合，可逆性抑制26S蛋白酶体活性，引起IKB聚集，阻止释放NF-KB，逆转NF-KB的活化而抑制肿瘤。该蛋白降解途径被阻断后，细胞内很多重要蛋白的代谢，包括核转录因子NF—KB和其抑制单位IKB、肿瘤抑制基因p53、细胞周期蛋白依赖性激酶抑制蛋白和多种促凋亡蛋白等出现紊乱，从而激活多条细胞凋亡通路，诱导MM细胞凋亡。阻断NF—KB可致骨髓瘤细胞黏附因子的表达下降，从而干扰由黏附因子介导的骨髓基质细胞产生白细胞介素-6的过程。硼替佐米同时可干扰与增生信号相关的丝裂原活化蛋白激酶p44/42途径，诱导细胞周期依赖性激酶抑制剂p21及p27的累积，当细胞周期依赖性激酶功能 被抑制时，细胞不能从G1期进入S期，从而导致细胞死亡。研究证实，恶性细胞株对蛋白酶体抑制的敏感性比非恶性细胞株高100～1000倍。当蛋白酶体活性被抑制后，正常细胞处于G0期属于被保护状态，而肿瘤细胞仍处于细胞周期，因此硼替佐米对MM细胞具有选择性杀灭作用。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. After the protein degradation pathway is blocked, many important proteins in the cell are metabolized, including the nuclear transcription factor NF-KB and its inhibitory unit IKB, tumor suppressor gene p53, 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. Studies have confirmed that 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.
硼替佐米(商品名：Valcade/万珂)是于2003经FDA批准上市的一款用于多发性骨髓瘤的注射用药物，可静脉注射或皮下注射给药，本品的推荐剂量为单次注射1.3mg/m2，每周注射2次，连续注射2周(即在第1、4、8和11天注射)后停药10天(即从第12至第21天)。3周为1个疗程，两次给药至少间隔72小时。在临床研究中，被确认完全缓解的患者再接受另外2个周期的万珂治疗，建议缓解的患者接受8个周期的万珂治疗。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.
据临床药动数据结果可见(FDA,，021602s043lbl)，目前上市制剂为静脉注射剂，FDA在2012年批准其皮下注射剂。在癌症患者的临床研究中：EC50＝1.48ng/ml，对蛋白酶体有效抑制(70％-80％)的起效浓度为2ng/ml，其上市的静脉注射剂给药后2-5分钟可达到Cmax＝223ng/ml，皮下注射剂给药后5-60分钟可达到Cmax＝20.4ng/ml，其Cmax远超过其起效浓度，会产生较大的毒副作用。并且药动学曲线表明其药效持续时间约为72h(>2ng/ml)，因此临床3天给药一次(在第1、4、7和11天注射给药，随后停药10天使得蛋白活性恢复至正常)；将硼替佐米开发成缓释制剂，使其在11天内维持血药浓度大于起效浓度2ng/ml，随后停药10天恢复其蛋白活性。使得患者给药一次后可长时间达到治疗效果，降低Cmax引起的毒性，提高患者顺应性，降低用药成本。因此将硼替佐米开发成缓释制剂的可行性较大；According to the results of clinical pharmacokinetic data (FDA, 021602s043lbl), the currently marketed preparations are intravenous injections, and the FDA approved its subcutaneous injections in 2012. In clinical studies of cancer patients: EC 50 = 1.48 ng / ml, effective inhibition of proteasome (70% - 80%), 2 ng / ml, 2-5 minutes after the onset of intravenous drug delivery When C max = 223 ng/ml is reached, C max = 20.4 ng/ml can be reached 5-60 minutes after subcutaneous injection, and its C max far exceeds its onset concentration, which causes greater toxic side effects. And the pharmacokinetic curve showed that the duration of its efficacy was about 72h (>2ng/ml), so it was administered once every 3 days (injected on days 1, 4, 7 and 11 and then stopped for 10 days to make the protein The activity was restored to normal; 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;
较大的化合物毒性和较高的血药浓度波动范围，导致硼替佐米注射制剂在临床运用的过程中，显示出较多的局限性：1)注射后虽可快速达蛋白酶体抑制所需的血药浓度水平，但药物吸收较快，血药浓度峰值高，导致硼替佐米的稳态血药浓度波动范围较大，稳态血药浓度峰值高于蛋白酶抑制所需浓度几十倍甚至上百倍，产生较严重的毒副作用；2)消除迅速，为维持体内蛋白酶体有效抑制所需血药浓度水平，需多次注射给药，患者顺应性差；3)注射后，药物吸收过快，毒性的产生，也限制了剂量的进一步推升，进而阻碍了药效的进一步提升。Larger compound toxicity and higher fluctuations in blood drug concentration have led to more limitations in the clinical application of bortezomib injection preparations: 1) Rapidly up to proteasome inhibition after injection Blood drug concentration level, but the drug absorption is fast, the peak plasma concentration is high, resulting in a large range of steady-state blood drug concentration of bortezomib. The peak value of steady-state blood drug concentration is several times higher than the concentration required for protease inhibition. One hundred times, causing more serious side effects; 2) rapid elimination, in order to maintain the level of blood drug concentration required for effective inhibition of proteasome in the body, multiple injections are required, and the patient has poor compliance; 3) after the injection, the drug is absorbed too fast, toxicity The production also limits the further increase of the dose, which hinders the further improvement of the efficacy.
为进一步改善硼替佐米的临床抗肿瘤疗效，并降低药物的毒副作用，提高患者顺应性，有必要提供一种可稳定维持蛋白酶体抑制所需血药浓度，并降低血药浓度波峰/波谷比值的优良组合物形式，本发明的目的就是开发一种硼替佐米药物组合物，通过控制其释放行为，精确调控硼替佐米于体内的吸收速率和吸收时间，进而控制体内血药浓度 水平及其波动范围，维持体内血药浓度于有效蛋白酶体抑制水平的长期稳态，提高硼替佐米的抗肿瘤疗效，减少用药后的不良反应。In order to further improve the clinical anti-tumor effect of bortezomib, reduce the side effects of drugs, and improve patient compliance, it is necessary to provide a blood concentration that can stably maintain the inhibition of proteasome and reduce the peak/valley ratio of blood concentration. In the form of an excellent composition, 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.
经专利检索，与硼替佐米有关的制剂专利包括：1)硼替佐米的注射用普通速释制剂，如：硼替佐米溶液制剂(WO2016001905)、注射用脂质体(CN200580045755.2，CN 101795671)、冻干粉制剂(CN 104586776A，CN102784114A，CN 105496960)；2)控释制剂，如：与拓扑酶联合用药的控释制剂(CN101336893A)，经专利检索结果可见，目前尚无关于硼替佐米单一用药长效缓控释制剂的相关研究。According to the patent search, 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.
为进一步提高硼替佐米的临床疗效，本发明公开了一种可精确调控硼替佐米血药浓度水平和波动范围的控释组合物，该组合物可控地调节蛋白酶体抑制所需血药浓度水平的长期维持，同时降低血药浓度波动范围，进而在提高肿瘤细胞的蛋白酶体抑制率和抗肿瘤疗效的同时，减少了肿瘤患者用药后的不良反应，增加患者服药的顺应性。In order to further improve the clinical efficacy of bortezomib, 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 long-term maintenance of the level, while reducing the fluctuation range of blood drug concentration, in order to improve the proteasome inhibition rate and anti-tumor efficacy of tumor cells, reduce the adverse reactions after drug administration, and increase the compliance of patients taking medication.
发明内容Summary of the invention
硼替佐米多次注射给药后，往往产生较高的稳态血药波峰/波谷比值(>100)，即较大的血药浓度波动，虽然该药物对蛋白酶体可逆性抑制，但仍然导致制剂存在众多安全性问题，而且存在多次注射的患者顺性差的问题，限制了其临床疗效的进一步提升和发挥。After multiple injections of bortezomib, a higher steady-state blood peak/valley ratio (>100) is often produced, ie a large fluctuation in blood concentration, although the drug reversibly inhibits the proteasome, but still results in There are many safety problems in the preparation, and the problem of poor responsiveness in patients with multiple injections limits the further improvement and exertion of clinical efficacy.
本发明的首要目的是针对硼替佐米的生物学性质和临床治疗的药效及安全性需求，提供一种体内吸收行为、血药浓度和蛋白酶体抑制水平可控的硼替佐米药物组合物，以进一步提高硼替佐米的临床疗效，减少肿瘤患者用药后的不良反应，并增加患者服药的顺应性。本发明涉及具有改进硼替佐米药物载量和/或体内吸收和/或生物利用度和/或血药浓度控制和/或酶抑制水平控制的新型药物的组合和它们作为唯一制剂或与其他疗法联合治疗癌症的用途。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. In order to further improve the clinical efficacy of bortezomib, reduce the adverse reactions after drug administration in patients with cancer, and increase the compliance of patients taking medication. 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.
本发明所提供的硼替佐米药物组合物中的活性成分硼替佐米，可以是硼替佐米的游离碱形式，也可以是其药理学上可接受的盐形式的化合物。因此，在本发明药物组合物中的活性成分硼替佐米包括硼替佐米的游离碱和其药理学上可接受的盐。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.
本发明提供了一种硼替佐米药物组合物，所述组合物包含0.1-200重量份，优选0.5-200重量份的活性成分硼替佐米，0.1-500重量份，优选0.5-500重量份的释放速率调节用辅料；0-1000重量份，优选0.1-300重量份，更优选0.1-100重量份，更优选0.1-10重量份的小分子调节剂；0-2000重量份，优选0.1-2000重量份的药用可注射溶剂。The present invention provides 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.
所述释放速率调节用辅料为选自可实现局部注射缓释效果的药用辅料，优选选自药用可生物降解储库型控释材料、药用油脂、药用表面活性剂等中一种或两种以上的组合； 具体地，药用可生物降解储库型控释材料为选自：醋酸异丁酸蔗糖酯(SAIB)、聚乳酸(PLA)、聚乳酸-羟基乙酸共聚物(PLGA)、聚乙二醇化的PLA/PLGA、PLGA-PEG-PLGA共聚物、聚原酸酯类、聚磷酸酯共聚物、脂肪酸甘油酯、三乙二醇聚(原酸酯)聚合物、壳聚糖、水溶性羧甲基壳聚糖、丝心蛋白、聚-β-羟基丁酸戊酸酯、聚丙交酯/丙交酯-聚乙二醇共聚物和/或其共混物、聚己内酯-聚乙二醇共聚物、聚β-羟基丁酸酯与聚乙二醇共混物和聚乳酸/羟乙酸共混物中的一种或两种以上的组合；所述药用表面活性剂为选自：注射用磷脂、Solutol HS 15、聚山梨醇酯、聚氧乙烯蓖麻油、聚氧乙烯脂肪酸酯、泊洛沙姆、磷脂酰胆碱(如DEPC或DOPC或它们的组合物)、磷脂酰甘油(如DPPG)、聚乙二醇、单硬脂酸甘油酯、明胶中的一种或两种以上的组合；所述药用油脂为选自：甘油、胆固醇、丙二醇酯、乙二醇酯、角鲨烯、硬脂酸、橄榄油、大豆油、椰子油、蓖麻油、芝麻油、玉米油、花生油、棉籽油、茶油、鱼油、甘油三脂(如油酸甘油三酯或辛酸甘油三酯)、药用油脂(甘油油酸或其与磷脂的混合物等)以及相应盐中的一种或两种以上的组合；和/或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. Or a combination of two or more; Specifically, 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-β-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-β-hydroxybutyrate and a polyethylene glycol blend and a polylactic acid/glycolic acid blend; the pharmaceutically acceptable surfactant is selected from the group consisting of: an injection Using phospholipids, Solutol HS 15, polysorbates, polyoxyethylene castor oil, polyoxyethylene fatty acid esters, poloxamers, phosphatidylcholines (such as DEPC or DOPC or combinations thereof), phosphatidylglycerol ( Such as DPPG), polyethylene glycol, glyceryl monostearate, gelatin or a combination of two or more; the medicinal oil is selected from the group consisting of: glycerin, cholesterol, and propylene Ester, glycol ester, squalene, stearic acid, olive oil, soybean oil, coconut oil, castor oil, sesame oil, corn oil, peanut oil, cottonseed oil, tea oil, fish oil, triglyceride (such as oleic acid glycerin a triester or caprylic acid triglyceride), a pharmaceutically acceptable oil or fat (glycerol oleic acid or a mixture thereof with a phospholipid, etc.) and a combination of one or more of the corresponding salts; and/or
其中，所述小分子调节剂为选自：乙酸、无水枸橼酸、抗坏血酸、氯化钙、苯甲酚、依地酸钙二钠、依地酸钠、甘氨酸、组氨酸、赖氨酸、盐酸、乳酸、单水乳糖、氯化镁、甘露醇、甲磺酸、蛋氨酸、苯酚、磷酸、无水磷酸氢二钾、醋酸钠、抗坏血酸钠、碳酸氢钠、亚硫酸氢钠、氯化钠、柠檬酸钠、氢氧化钠、磷酸钠、磷酸氢二钠、磷酸二氢钠、磷酸钾、磷酸氢二钾、磷酸二氢钾、碳酸钠、碳酸氢钠、葡甲胺、鱼精蛋白、对羟基苯甲酸丙酯、胆固醇、植物甾醇、精氨酸、三乙醇胺、葡萄糖、山梨醇、蔗糖、酒石酸、氨丁三醇、醋酸锌、氯化锌、葡萄糖中的一种或两种以上的组合；和/或Wherein, 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, glucose, sorbitol, sucrose, tartaric acid, tromethamine, zinc acetate, zinc chloride, and glucose Combination; and/or
所述药用可注射溶剂为水、苯甲醇、氯丁醇、二甲亚砜、甲基吡咯烷酮、二甲基乙酰胺、丙二醇、聚乙二醇、聚乙二醇(单)甲醚、三乙酸甘油酯、苯甲酸苄酯、甘油糖醛、甘油缩甲醛、丙二醇、乙醇、乙二醇二***中的一种或两种以上的组合。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.
本发明提供的药物组合物的贮存形式可以是溶液、混悬液、冻干粉或预装药物粉末或溶液的注射器形式，可供皮下、皮内、肌肉等部位的注射或埋植。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.
本发明提供的药物组合物可选自可供局部注射的或埋植用的混悬剂，油针制剂，缓释微球，植入凝胶，多囊脂质体及其他可应用的储库型缓控释局部注射用制剂(如SABER delivery system和Camurus FluidCrystal injection***等)等。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.).
本发明提供的药物组合物中注射前的单位制剂中药物活性成分的含量(单次注射制剂中含药量)约为0.1-200mg，优选制剂含药量为0.5-100mg，更优选1-50mg，甚至更优选1-20mg，人体上所需的单次局部注射或埋值的体积为0.5-2mL，优选每次注射或埋植的制剂量为小于1mL。 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.
鉴于硼替佐米对蛋白酶体的高强度抑制活性，长期的高浓度抑制可能导致机体难以耐受的毒副作用，因此，不排除每一次或多次用药后，给予机体一定“药物假期”的给药形式，即用药后一段时间，待药物吸收并消除后，再给予机体一定的恢复周期，才能再次用药。In view of the high-intensity inhibitory activity of bortezomib on the proteasome, long-term high-concentration inhibition may lead to toxic side effects that are difficult to be tolerated by the body. Therefore, administration of a certain "drug holiday" to the body after each or more administrations is not excluded. The form, that is, after a period of administration, after the drug is absorbed and eliminated, the body is given a certain recovery period before it can be used again.
本发明提供的硼替佐米药物组合物具有可控的释药行为，注射或埋植给药后，在预定的时间段内，在符合漏槽条件的释放介质中，其释放行为和释放量可控，在水性介质中，37℃条件下，1小时内释放量小于硼替佐米总量的20％，优选小于10％，甚至可小于5％；24h释放量小于硼替佐米总量的40％，优选小于30％，甚至可小于20％；90％药物释放时间>3天，甚至可大于7天，大于10天或大于15天。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.
与目前的速效注射剂相比，本发明所提供的药物组合物注射给药后，可快速达到有效抗肿瘤蛋白酶体抑制所需的血药浓度水平，并可避免血药浓度波动，维持在有效的血药浓度下几天，甚至十几天。该有效血药浓度可几天至十几天维持在1-200ng/mL的范围内，甚至血药浓度维持在1.5-100ng/mL，甚至血药浓度维持在2-50ng/mL。血药浓度波动的降低以及长期高效的蛋白酶体抑制效果，有望提高抗肿瘤疗效，同时减少毒性的产生，实现对肿瘤患者更高效低毒的可调控化治疗和给药频次的调控。Compared with the current quick-acting injection, 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.
本发明提供了所述硼替佐米药物组合物在制备用于治疗和/或预防多发性骨髓瘤等癌症的药物中的用途。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.
本发明提供的硼替佐米药物组合物可用于多发性骨髓瘤等癌症的临床治疗。The bortezomib pharmaceutical composition provided by the invention can be used for clinical treatment of cancers such as multiple myeloma.
与普通速释制剂相比，具有如下优点：Compared with ordinary immediate release preparations, it has the following advantages:
1)可实现药物的可控化释放和吸收，提供精确的体内血药浓度和长时间稳定的蛋白酶体抑制水平，药效持久；1) 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;
2)可控的药物吸收速率，控制血药浓度水平和波动范围，避免患者用药后过多的不良反应；2) Controllable drug absorption rate, control blood drug concentration level and fluctuation range, avoid excessive adverse reactions after drug administration;
3)单次注射或埋植后，可维持较长时间的有效蛋白酶体抑制，减少了普通制剂经常注射的繁琐过程，更加方便临床用药；3) After a single injection or implantation, the effective proteasome inhibition can be maintained for a long time, which reduces the cumbersome process of frequent injection of common preparations, and is more convenient for clinical use;
4)由于可控的血药浓度及其波动范围，安全窗口较大，临床治疗过程中，临床剂量和给药方案可灵活调节，有望进一步提高治疗剂量，增强抗肿瘤疗效。4) Due to the controllable blood concentration and its fluctuation range, the safety window is large. During clinical treatment, 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.
为更好地阐述本发明提供的硼替佐米药物组合物性质，下文的叙述是对于本发明的详细说明，对本发明的范围不构成任何限制。In order to better illustrate the nature of the bortezomib pharmaceutical composition provided by the present invention, the following description is a detailed description of the present invention and is not intended to limit the scope of the present invention.
附图说明 DRAWINGS
图1显示实施例1硼替佐米原位沉淀型凝胶制剂的体外释放曲线。Figure 1 shows the in vitro release profile of the bortezomib in situ precipitated gel formulation of Example 1.
图2显示实施例2硼替佐米缓释微球的体外释放曲线。Figure 2 shows the in vitro release profile of the bortezomib sustained release microspheres of Example 2.
图3显示实施例4硼替佐米多囊脂质体的体外释放曲线。Figure 3 shows the in vitro release profile of the bortezomib polycapsule liposomes of Example 4.
图4显示实施例6硼替佐米原位温敏型凝胶制剂的体外释放曲线。Figure 4 shows the in vitro release profile of the bortezomib in situ temperature sensitive gel formulation of Example 6.
图5显示对比实施例1的速释硼替佐米制剂和实施例1中的硼替佐米原位凝胶储库型注射液的犬体内药时曲线图。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.
具体实施方式detailed description
1.多囊脂质体Polycystic liposome
本发明提供的多囊脂质体(Liposomes)主要是由胆固醇和磷脂等组成的类似于生物膜双分子层结构封闭的微小囊泡，是一种新型的药物载体。脂质体按结构可分为3类：单室脂质体(ULV)、多室脂质体(MLV)和多囊脂质体(MVL)，其中前两者为同心脂质体，而MVL则属于非同心脂质体，MVL是由非同心的类脂双分子囊泡紧密堆积而成的聚集体，是一种传递药物的新型脂质体。这种脂质体装载药物后，注射进入体内形成药物储库，产生良好的缓释作用，这样不仅可减少患者的用药次数，还能提高治疗的依从性，已成为众多学者研究的热点。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. After the liposome is loaded with the drug, 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.
本发明的硼替佐米药物组合物可以为硼替佐米多囊脂质体形式，其中所述硼替佐米多囊脂质体组合物包含活性成分硼替佐米、脂质成分(包括油脂和表面活性剂)以及非必须的可药用的pH/渗透压调节剂中的一种或两种以上的组合；其中，所述硼替佐米多囊脂质体组合物包含0.1-200重量份，优选0.5-100重量份，更优选1-50重量份的，甚至更优选1-20重量份的活性成分硼替佐米，0.1-300重量份、优选0.1-200重量份的脂质成分，和非必须的0-1000重量份，优选0.1-300重量份，更优选0.1-100重量份，更优选0.1-10重量份的脂质膜流动性调节剂/pH/渗透压调节剂。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 fluidity regulator/pH/osmotic pressure regulator.
所述硼替佐米是装载至多囊脂质体内部的唯一活性成分；该制剂组合物可以包括未被多囊脂质体包裹的游离硼替佐米，未被多囊脂质体装载的游离硼替佐米的量一般小于组合物中硼替佐米总量的20％，优选小于10％。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.
所述脂质成分为至少一种两亲性脂质和/或至少一种中性脂质；所述两亲性脂质为选自磷脂酰胆碱、磷脂酰甘油、相应盐中的一种或两种以上成分的组合；在某些实例中，磷脂酰甘油可以是DPPG，在某些实例中，磷脂酰胆碱可以为DEPC或DOPC或它们的组合物；所述中性脂质可为选自乙二醇酯、角鲨烯、甘油、甘油三酯和丙二醇酯等中的 一种或两种以上的组合，在具体的实例中甘油三脂可以选自油酸甘油三酯和辛酸甘油三酯。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. Or a combination of two or more components; in certain instances, 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 One or a combination of two or more, in a specific example, the triglyceride may be selected from the group consisting of oleic acid triglyceride and caprylic acid triglyceride.
在某些实例中，组合物优选包括脂质膜流动性调节剂、渗透压调节剂或pH调节剂；所述脂质膜流动性调节剂可以选自胆固醇、植物甾醇等；所述pH调节剂为选自非有机酸、有机酸、非有机碱、有机碱中的一种或两种以上的组合，具体地说pH调节剂选自盐酸、磷酸、酒石酸、组氨酸、赖氨酸、丁氨酸、氨丁三醇中的一种或两种以上的组合；渗透压调节剂选自氯化钠、葡糖糖、蔗糖和甘露醇中的一种或两种以上的组合；本发明的多囊脂质体的外相水溶液pH范围可在4.0-9.0之间。In certain instances, 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. One or a combination of two or more of lysine and tromethamine; 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.
多囊脂质体组合物制剂中的活性成分硼替佐米的单次注射给药量范围是0.1-200mg，在某些实例中，未包裹的游离硼替佐米量占组合物中硼替佐米总量的0-10％。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.
本发明提供的多囊脂质体组合物，可静脉、皮下或肌肉注射给药，优选皮下注射给药。The multivesicular liposome compositions provided by the present invention can be administered intravenously, subcutaneously or intramuscularly, preferably by subcutaneous injection.
本发明的多囊脂质体的制备方法采用本领域中的常规方法，例如采用复乳法，具体地说，需要包括以下5个步骤：(1)先将处方量的脂质成分溶解于易挥发的有机溶剂(通常为氯仿或氯仿与***的混合液)形成油相，将处方量的硼替佐米溶于水中形成含药的水溶液(第一水相)，再以合适的油水体积比(体积比为1:10-12:10，v/v)将含药的水溶液(第一水相)与脂质的有机相(油相)混合，在室温下超声或机械剪切一定时间制备出均匀的油包水(W/O)型初乳；(2)吸取形成的W/O型初乳，按一定比例注入第二水相缓冲液(体积比为1:10-5:10，v/v)，在30℃条件下机械剪切再次乳化形成稳定的水包油包水(W/O/W)型复乳；(3)将复乳转移至锥形瓶中，以惰性气体(如氮气)除去复乳中的有机溶剂(***、氯仿、二氯甲烷等)，可在表面通入氮气或将氮气导管伸入锥形瓶底部来除去有机溶剂；(4)必要时，可用适用于储存和生理上可接受的盐溶液(如0.9％氯化钠溶液)置换第二水相，浓缩；(5)调整药物含量、根据含量灌装。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.
所用脂质一般包括中性脂质(常用三酰甘油)、磷脂和胆固醇等，中性脂质是MVL制备过程中重要的部分，否则只能得到普通脂质体。制备初乳的方法有：超声、高速分散、乳匀机、喷嘴雾化等，实验室中也常采用涡旋混合器或高速分散器进行乳化。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.
处方中包封的介质及脂质的种类不同，都会使药物的释放速度不同，其中中性脂质甘油三酯不同的碳链长短可调节药物的释放速度。除此之外，制备MVL时搅拌的时间、温度、速度、外水相体积、氮气流速、分离游离药物的方法等对其粒径、包封率、包封容积和稳定性也会产生一定影响，调节以上工艺条件可获取不同释放速率的硼替佐米多囊脂质体。 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. In addition, 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.
本发明所提供的多囊脂质体，于6小时内释放量小于制剂中硼替佐米总量的20％，优选小于10％，甚至小于5％；24h释放量小于硼替佐米总量的40％，优选小于30％，甚至小于20％；90％药物释放时间>3天。本发明所提供的药物组合物注射给药后，可快速达到有效抗肿瘤蛋白酶体抑制所需的血药浓度水平，并可避免血药浓度波动，维持在有效的血药浓度下几天，甚至数十天。该有效血药浓度可几天至几十天维持在1-200ng/mL的范围内，甚至血药浓度大于1.5ng/mL<C<100ng/mL维持7天以上。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.
2.混悬剂2. Suspension
本发明提供的硼替佐米药物组合物可以通过硼替佐米混悬剂的形式实施，以实现所述的释放行为。所述混悬剂可选自水性介质混悬剂或油性介质混悬剂。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.
硼替佐米混悬剂包含活性成分硼替佐米，释放速率调节用辅料，药用可注射溶剂，和/或混悬剂稳定剂，和/或等渗剂、缓冲剂等；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;
其中，所述硼替佐米混悬剂包含0.1-200重量份，优选0.5-100重量份，更优选1-50重量份的，甚至更优选1-20重量份的活性成分硼替佐米；0-2000重量份，优选0-300重量份，更优选0.5-300重量份的药用可注射溶剂；0.1-500重量份，优选0.5-500重量份的释放速率调节用辅料；0-1000重量份，优选0.1-300重量份，更优选0.1-100重量份，更优选0.1-5重量份的等渗剂和/或缓冲剂。Wherein 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.
在某些实施例中，所述释放速率调节用辅料可选自药用油脂、表面活性剂或聚合物，药用油脂可包括椰子油、蓖麻油、芝麻油、玉米油、大豆油、花生油、棉籽油、茶油、鱼油、甘油、胆固醇、丙二醇酯、乙二醇酯、角鲨烯、硬脂酸、甘油三脂(如油酸甘油三酯或辛酸甘油三酯)、甘油油酸或其与磷脂的混合物以及相应盐中的一种或两种以上的组合；所述表面活性剂可包括注射用磷脂、聚山梨醇酯80、聚山梨醇酯20、聚氧乙烯蓖麻油50、聚氧乙烯蓖麻油60、泊洛沙姆和聚氧乙烯脂肪酸酯中的一种或两种以上组合，聚合物可为选自羧甲基纤维素钠、醋酸乙烯酯共聚物、泊洛沙姆、聚乙二醇、羟基乳酸聚合物、聚酯、聚多糖和聚维酮K12/K17中的一种或两种以上的组合。In certain embodiments, 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. Oil, tea oil, fish oil, glycerin, cholesterol, propylene glycol ester, ethylene glycol ester, squalene, stearic acid, triglyceride (such as oleic acid triglyceride or caprylic acid triglyceride), glycerol oleic acid or a mixture of phospholipids and a combination of one or more of the corresponding salts; 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.
所述药用可注射溶剂为选自：水、苯甲醇、氯丁醇、二甲亚砜、甲基吡咯烷酮、二甲基乙酰胺、丙二醇、聚乙二醇、聚乙二醇(单)甲醚、三乙酸甘油酯、苯甲酸苄酯、油酸乙酯、甘油糖醛、甘油缩甲醛、丙二醇、乙醇、乙二醇二***中的一种或两种以上的组合。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) A One or a combination of two or more of ether, triacetin, benzyl benzoate, ethyl oleate, glycerol aldehyde, glycerol formal, propylene glycol, ethanol, ethylene glycol diethyl ether.
所述缓冲剂可选自磷酸钠、磷酸氢二钠、磷酸二氢钠、柠檬酸钠、磷酸钾、磷酸氢二钾、磷酸二氢钾、碳酸钠、碳酸氢钠、葡甲胺、精氨酸、三乙醇胺和枸橼酸中的一种或两种以上的组合。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. One or a combination of two or more of an acid, triethanolamine, and citric acid.
所述等渗剂可选自氯化钠、蔗糖、葡糖糖和甘露醇中的一种或两种以上的组合。 The isotonic agent may be selected from one or a combination of two or more of sodium chloride, sucrose, glucose, and mannitol.
本发明提供的混悬剂可以是纳米混悬剂或微米混悬剂，纳米混悬剂粒径范围是50-800nm，微米混悬剂的粒径范围是1-18μm。可通过本领域常见的均质破坏法等制备，如首先将混悬剂稳定剂溶于水中，将活性药物置于以上含有稳定剂的溶液，经过初步的剪切破碎后，在一定温度下，循环均质破碎，获取粒径均匀的混悬剂。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 μm. 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.
本发明提供的混悬剂中的活性成分硼替佐米的单次给药量范围是0.1-200mg，优选0.5-100mg；本发明提供的硼替佐米混悬剂可皮下或肌肉注射给药，优选皮下注射给药。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.
3.原位凝胶3. In situ gel
原位凝胶制剂属于储库型局部注射用制剂的一种，是近年来缓控型注射剂领域的研究热点，它是将药物和聚合物溶于适宜的溶剂中，局部皮下注射，在给药部位，聚合物在生理条件下凝固而形成半固体或固体药物贮库。原位凝胶克服了普通乳剂、脂质体、微球和胶束的缺点，具有可用于病变部位的局部给药、延长释药周期、降低给药剂量和药物不良反应、避免植入剂开刀植入时的痛苦、工艺相对简单等优点。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.
本发明提供的硼替佐米药物组合物可以通过硼替佐米原位凝胶***的形式实现所述的释放行为，其特征在于，该原位凝胶***包含活性成分药物硼替佐米、适宜的溶剂、释放速率调节用凝胶形成材料。其中，所述硼替佐米原位凝胶***包含0.1-200重量份，优选0.5-100重量份，甚至更优选1-50重量份，甚至更优选1-20重量份的活性成分硼替佐米；0.1-2000重量份，优选50-2000重量份，更优选100-1000重量份的可药用的注射用溶剂；0.1-500重量份，优选0.5-250重量份，甚至更优选1-100重量份的所述释放速率调节用凝胶形成材料。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. Wherein 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.
所述硼替佐米原位凝胶***可以本领域公知的方式制备，具体地，例如，可用聚乙二醇甲醚或N-甲基吡咯烷酮等溶剂溶解药用聚合物聚乳酸或聚乳酸-羟基乙酸共聚物等释放速率调节用凝胶形成材料，形成溶液，该溶液可直接溶解活性药物硼替佐米，或与活性药物分别预装在无菌注射器后，临用前再溶解药物。溶解药物后的溶液，局部注射至人体，凝胶形成材料溶解用溶剂在局部快速吸收，部分溶解药物也随溶剂的吸收而快速吸收，而凝胶材料体内遇水性环境，形成半固体或固体状凝胶，而溶解或分散至凝胶***内的大部分活性药物，则随着凝胶的降解和溶蚀缓慢释放，实现体内药物平稳吸收和血药浓度维持。The bortezomib in situ gel system can be prepared in a manner well known in the art. Specifically, for example, 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.
本发明所述的原位凝胶***中的适宜的溶剂可为选自水、N-甲基吡咯烷酮、聚乙二醇(单)甲醚、三乙酸甘油酯、苯甲酸苄酯、甘油糖醛、甘油缩甲醛、丙二醇、乙醇、乙二醇二***、苯甲醇、二甲亚砜中的一种或两种以上的组合。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.
所述释放速率调节用凝胶形成材料包括：聚乳酸(PLA)、聚乳酸-羟基乙酸共聚物(PLGA)、聚原酸酯、醋酸异丁酸蔗糖酯、PLGA-PEG-PLGA共聚物、脂肪酸甘油酯、 聚乙二醇化的PLA/PLGA、聚己内酯-聚乙二醇共聚物、三乙二醇聚(原酸酯)聚合物、泊洛沙姆中的一种或两种以上的组合。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.
原位凝胶***中的活性成分硼替佐米的单次给药量范围是0.1-200mg，优选0.5-100mg，更优选1-50mg，甚至更优选1-20mg。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.
本法明所提供的硼替佐米原位凝胶***，于6小时内释放量小于制剂中硼替佐米总量的20％，甚至小于10％；24h释放量小于硼替佐米总量的40％，甚至小于30％；90％药物释放时间>3天。本发明所提供的硼替佐米原位凝胶***注射给药后，可快速达到有效抗肿瘤蛋白酶体抑制所需的血药浓度水平，并可避免血药浓度波动，维持在有效的血药浓度下几天，甚至数十天。该有效血药浓度可几天至几十天维持在1-200ng/mL的范围内，甚至血药浓度大于1.5ng/mL<C<100ng/mL维持7天以上。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.
本发明提供的原位凝胶***可以溶液状态短期贮存，或以预分装药物和溶剂的注射器形式贮存。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.
本发明提供的原位凝胶***可静脉、皮下或肌肉注射给药，优选皮下和肌肉注射给药。The in situ gel system provided by the present invention can be administered intravenously, subcutaneously or intramuscularly, preferably subcutaneously and intramuscularly.
4.微球4. Microspheres
本发明提供的微球是指药物溶解或分散在缓释高分子材料基质中形成的微小球状实体，粒径较小，属于基质型骨架微粒。微球具有高效无毒、释药速率恒定以及粒径可控的优点，已广泛应用于长效注射剂的研制。微球注射剂的药物释放速率主要由聚合物传递***决定。当微球注射入皮下或肌内后，药物可从微球基体内缓慢释放，骨架材料可逐渐水解溶蚀，降解的最后产物为CO2和水，易为机体吸收而不会引起不良反应。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. 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.
本发明所述释放行为的药物组合物可以硼替佐米微球的方式提供，所述硼替佐米微球包含活性成分硼替佐米和释放速率调节用聚合物材料。本发明的缓释微球包含0.1-200重量份，优选0.5-100重量份，甚至更优选1-50重量份，甚至更优选1-20重量份的活性药物硼替佐米，和0.1-500重量份，优选0.2-250重量份，甚至更优选1-200重量份的释放速率调节用聚合物。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.
本发明提供的微球制剂为干燥粉末，临用前，需用可注射用水或其他溶剂混悬均匀后注射；所述其他溶剂为不影响微球稳定性的注射用溶剂，优选选自聚乙二醇、甘油、0.1wt％-1wt％聚山梨醇酯80的水溶液中的一种或两种以上组合。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. One or a combination of two or more of an aqueous solution of a diol, glycerin, and 0.1% by weight to 1% by weight of polysorbate 80.
所述硼替佐米缓释微球可以用本领域公知的方式制备，具体地，可将活性药物硼替佐米与释放速率调节用的聚合物材料溶解于适宜的溶剂后，以智能化喷雾干燥静电收集***喷雾干燥收集制备；硼替佐米与适宜的释放调节用聚合物材料如聚乳酸-羟基乙酸共聚物(PLGA)，首先溶解于溶剂如二氯甲烷中，以0.2-1ml/min的速率缓慢注射入喷 雾干燥静电***(如瑞士步琦BUCHI小型喷雾干燥仪B-290)，干燥温度为40℃-80℃左右，在喷雾干燥过程，实时监测微球粒径，调节进样速率、喷雾频率，加热温度和通风量大小，待喷雾干燥结束后，收集静电收集***壁上的微球粉末即可，药物和聚合物溶液的浓度，***的进样速率，喷雾频率，干燥温度和通风量等对微球的理化性质和产率有较大影响，控制以上影响因素的条件，可获取粒径均匀的缓释微球制剂，本发明提供的缓释微球粒径一般在0.5～20μm之间。本发明提供的缓释微球局部注射至人体内，药物会随着释放速率调节用聚合物基质的降解和溶蚀缓慢释放，实现体内药物平稳吸收和血药浓度维持。所述释放速率调节用聚合物基质材料包括：聚乳酸(PLA)、聚乳酸-羟基乙酸共聚物(PLGA)、聚乙二醇化的PLA/PLGA、壳聚糖、水溶性羧甲基壳聚糖、丝心蛋白、聚-β-羟基丁酸戊酸酯、聚丙交酯/丙交酯-聚乙二醇共聚物共混物、聚β-羟基丁酸酯与聚乙二醇共混物、聚乳酸/羟乙酸共混物以及药学可应用的局部注射用缓控释材料中的一种或两种以上组合。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. Injection into the spray Fog drying static system (such as Swiss Buqi BUCHI Mini Spray Dryer B-290), 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. Under the conditions of controlling the above influencing factors, 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 μm. 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-β-hydroxybutyrate valerate, polylactide/lactide-polyethylene glycol copolymer blend, poly-β-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.
本发明提供的微球***可以固体粉末形式长期贮存。The microsphere system provided by the present invention can be stored for a long period of time in the form of a solid powder.
本发明提供的缓释微球制剂可静脉、皮下或肌肉注射给药，优选皮下和肌肉注射给药。The sustained release microsphere preparation provided by the present invention can be administered intravenously, subcutaneously or intramuscularly, preferably subcutaneously and intramuscularly.
5、油针制剂5, oil needle preparation
本发明提供的硼替佐米药物组合物可以通过硼替佐米油针制剂的形式实施，以实现所述的释放行为。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.
硼替佐米油针制剂包含活性成分硼替佐米，释放速率调节用辅料和/或药用可注射溶剂，和/或小分子调节剂；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;
其中，所述硼替佐米油针制剂包含0.1-200重量份，优选0.5-100重量份，更优选1-50重量份，甚至更优选1-20重量份的活性成分硼替佐米0.1-500重量份，优选0.5-500重量份的释放速率调节用辅料；0-300重量份，优选0-100重量份，更优选0.1-100重量份的药用可注射溶剂；0-1000重量份，优选0.1-300重量份，更优选0.1-100重量份，更优选0.1-10重量份的小分子调节剂。Wherein 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.
在某些实施例中，所述释放速率调节用辅料为选自药用油脂、表面活性剂或聚合物，例如，所述表面活性剂为选自注射用磷脂、聚山梨醇酯80、聚山梨醇酯20、聚氧乙烯蓖麻油50、聚氧乙烯蓖麻油60、泊洛沙姆和聚氧乙烯脂肪酸酯中的一种或两种以上组合；所用药用油脂为选自：甘油、胆固醇、丙二醇酯、乙二醇酯、角鲨烯、硬脂酸、甘油三脂(如油酸甘油三酯或辛酸甘油三酯)、甘油油酸或其与磷脂的混合物以及相应盐中的一种或两种以上的组合；所述聚合物为选自羧甲基纤维素钠、醋酸乙烯酯共聚物、泊洛沙姆、聚乙二醇、羟基乳酸聚合物、聚酯、聚多糖和聚维酮K12/K17中的一种或 两种以上的组合；In certain embodiments, the release rate adjusting excipient is selected from the group consisting of medicinal oils, surfactants, or polymers. For example, the surfactant is selected from the group consisting of phospholipids for injection, polysorbate 80, and polysorbate. One or a combination of two or more of the alcohol ester 20, the polyoxyethylene castor oil 50, the polyoxyethylene castor oil 60, the poloxamer and the polyoxyethylene fatty acid ester; 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;
所述药用可注射溶剂可选自苯甲醇、氯丁醇、二甲亚砜、甲基吡咯烷酮、二甲基乙酰胺、丙二醇、聚乙二醇、聚乙二醇(单)甲醚、三乙酸甘油酯、苯甲酸苄酯、油酸乙酯、甘油糖醛、甘油缩甲醛、丙二醇、乙醇、乙二醇二***中的一种或两种以上的组合；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;
所述小分子调节剂为选自磷酸钠、磷酸氢二钠、磷酸二氢钠、柠檬酸钠、磷酸钾、磷酸氢二钾、磷酸二氢钾、碳酸钠、碳酸氢钠、葡甲胺、精氨酸、三乙醇胺、枸橼酸、氯化钠、葡糖糖、蔗糖和甘露醇中的一种或两种以上的组合。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.
本发明提供的油针制剂可通过本领域常见的方法制备，如首先将活性药物硼替佐米溶解于药用可注射溶剂中，再加入释放调节用辅料和小分子调节剂混合均匀，或直接将活性药物硼替佐米、释放速率调节用辅料和小分子调节剂溶解于药用可注射溶剂中，制得油针制剂。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.
本发明提供的油针制剂中的活性成分硼替佐米的单次给药量范围是0.1-200mg，优选0.5-100mg；本发明提供的硼替佐米油针制剂可皮下或肌肉注射给药，优选皮下注射给药。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.
实施例Example
以下实施例一般性地记载了本发明典型组合物的制备方法和/或表征结果，所有的百分比均为重量百分比，除非另有指明。以下实施例是对本发明的具体说明，而不应该认为是对本发明范围的限制。在以下实施例中，未详细描述的各种过程和方法采用本领域中公知的常规方法。The following examples generally describe the preparation and/or characterization of typical compositions of the invention, all percentages being by weight unless otherwise indicated. The following examples are illustrative of the invention and are not to be construed as limiting the scope of the invention. In the following examples, various processes and methods not described in detail employ conventional methods well known in the art.
实验动物：比格犬雌雄各半，体重8～10kg。来源均为北京玛斯生物技术有限公司。受试动物在试验日前14天均在上海药物研究所实验动物中心的试验场所进行适应性饲养。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.
实施例1硼替佐米原位沉淀型凝胶制剂的制备(储库型制剂)Example 1 Preparation of Bortezomib In-situ Precipitated Gel Formulation (Reservoir Formulation)
Figure PCTCN2017116587-appb-000002
Figure PCTCN2017116587-appb-000002
将处方量的聚乙二醇化PLA(分子量为5000)加入装有N-甲基吡咯烷酮的容器中，搅拌2小时，使其呈现均一的状态，得到空白凝胶制剂；再加入处方量的硼替佐米至空白凝胶制剂中，缓慢搅拌1小时，得到均匀的溶液即为原位沉淀型凝胶注射液。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.
释放度实验： Release test:
取所得的凝胶注射液注入装有蒸馏水的小瓶中，加盖密封，置于恒温水浴振荡器中(37℃，频率60rpm，振幅：24mm)，分别于设定的时间点，将瓶中的溶液全部取出，再补加相应体积的相同的蒸馏水介质，放回水浴振荡器。取出的释放液经10000rpm离心5min后，精密量取上清液20μl滤液注入液相色谱仪，记录色谱图，计算释放百分率，并绘制释放曲线，结果见图1.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 μl 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.
图1结果显示：原位沉淀型凝胶注射剂在12小时的释放度约为13％，24小时的释放度约为19％，120小时释放60％左右。持续释放的时间达6天以上。The results in Figure 1 show that the in situ precipitated gel injection has a release of about 13% at 12 hours, a release rate of about 19% at 24 hours, and about 60% at 120 hours. The duration of sustained release is more than 6 days.
实施例2硼替佐米微球的制备Example 2 Preparation of Bortezomib Microspheres
Figure PCTCN2017116587-appb-000003
Figure PCTCN2017116587-appb-000003
以二氯甲烷溶解硼替佐米和PLGA，以0.2ml/min-0.5ml/min的进样速率，注入到干燥温度为65℃、喷雾频率为120kHz、通风量为70L/min的BUCHI B-290喷雾干燥静电收集***，制备粒径均匀的微球，80％的微球粒径为0.5-10μm。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. Spray drying an electrostatic collection system to prepare microspheres of uniform particle size, 80% of the microspheres having a particle size of 0.5-10 μm.
释放度实验：Release test:
实施例2的硼替佐米微球置于生理等渗PBS溶液(pH 7.4)的释放介质中孵育，37℃，100r/min条件下，在预定的时间点，取溶出液5ml，10000rpm离心5min后，精密量取上清液20μl滤液注入液相色谱仪，记录色谱图，并作出药物累积释放曲线图，见图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 μl of the supernatant into the liquid chromatograph, record the chromatogram, and make a cumulative drug release profile, as shown in Figure 2.
图2显示：缓释微球于1小时内释放硼替佐米量小于20％，120小时内释放20％左右，192小时时仍持续释药，累积释放量不到30％。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%.
实施例3硼替佐米混悬剂的制备Example 3 Preparation of Bortezomib Suspension
Figure PCTCN2017116587-appb-000004
Figure PCTCN2017116587-appb-000004
硼替佐米混悬剂的制备包括如下步骤：(1)将助悬剂羧甲基纤维素钠加入适量的注射用水，并加热至80℃，搅拌，使其呈现均一的状态，得到分散介质1，备用；(2)将硼替佐米原料药研磨后与润湿剂聚山梨醇酯20混匀，加入注射用水制成混悬液；(3)在搅拌状态下将混悬液缓慢加入分散介质1中；(4)加入枸橼酸、柠檬酸钠，并加入适 量的水定容；(5)将定容好的混悬液不断搅拌60-120min，使其充分混匀；(6)将混匀的制剂分装于灭菌干燥的安瓿瓶中熔封或玻璃瓶中封口，即得硼替佐米混悬剂。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.
实施例4硼替佐米多囊脂质体的制备Example 4 Preparation of Bortezomib Polycapsule Liposomes
Figure PCTCN2017116587-appb-000005
Figure PCTCN2017116587-appb-000005
硼替佐米多囊脂质体的制备包括以下步骤：(1)先将处方量的胆固醇、二油酰磷脂酰胆碱(DOPC)、二棕榈酰磷脂酰甘油(DPPG)、三油酸甘油酯溶解于适量的氯仿-***(1:1，v/v)溶液中，作为脂质相；(2)再将处方量的硼替佐米、蔗糖用适量60mM的盐酸溶液溶解，作为内水相；(3)将上述内水相缓慢加入脂质相上层，用高速剪切匀浆机以14000rpm的速度搅拌8min，得W/O型初乳；(4)将上述初乳加入到含有5mg/ml葡萄糖和40mmol/L赖氨酸的外水相中，用高速剪切匀浆机以6000rpm的速度混合40s，形成W/O/W复乳；(5)将复乳转移至盛有外水相的锥形瓶中，通以氮气于37℃水浴除去复乳中的***和氯仿，得多囊脂质体混悬液；(6)向锥形瓶内加入适量的生理盐水，然后6000rpm离心10min分离脂质体。弃去上清液，并将沉淀物再分散于适量的生理盐水中，再离心沉淀，如此循环操作3次，富集沉淀，沉淀用适量生理盐水稀释，得硼替佐米多囊脂质体。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 aqueous phase, mixed with a high-speed shear homogenizer at 6000rpm for 40s to form W/O/W double emulsion; (5) Transfer the double emulsion to the external aqueous phase In the conical flask, the ether and chloroform in the double emulsion were removed by nitrogen in a water bath at 37 ° C, and the polycapsule liposome suspension was added; (6) an appropriate amount of physiological saline was added to the Erlenmeyer flask, and then centrifuged at 6000 rpm for 10 min. 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.
释放度实验：Release test:
称取实施例4中的硼替佐米多囊脂质体混悬液，用生理盐水稀释，将所得的混悬液置于37℃恒温摇床(转速为100rpm)中，在预定的时间点取出3ml样品，并补加相同体积的生理盐水；将取出的样品以10000rpm的转速离心5min，精密量取上清液20μl，注入液相色谱仪，记录色谱图，计算释放百分率，并绘制释放曲线，结果见图3。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 μl, inject into the liquid chromatograph, record the chromatogram, calculate the release percentage, and draw the release curve. The results are shown in Figure 3.
图3结果显示：实施例4的多囊脂质体在12小时释放约为10％，24小时约为19％，72小时释放约40％，144小时释放约为70％，持续释放的时间能够达到6天以上。The results in Figure 3 show that the multivesicular liposomes of Example 4 released about 10% at 12 hours, about 19% at 24 hours, about 40% at 72 hours, and about 70% at 144 hours, with sustained release time. More than 6 days.
实施例5硼替佐米油针制剂的制备Example 5 Preparation of Bortezomib Oil Needle Formulation
Figure PCTCN2017116587-appb-000006
Figure PCTCN2017116587-appb-000006
Figure PCTCN2017116587-appb-000007
Figure PCTCN2017116587-appb-000007
称取处方量的苯甲醇和注射用芝麻油，涡旋2min，混合均匀，后加入处方量的硼替佐米原料药，涡旋5min，超声2min，并搅拌1-2小时，使其呈现均匀的状态，即得硼替佐米油针制剂。Weigh the prescribed amount of benzyl alcohol and sesame oil for injection, vortex for 2 min, mix well, then add the prescribed amount of bortezomib bulk drug, vortex for 5 min, sonicate for 2 min, and stir for 1-2 hours to make it uniform. That is, a bortezomib oil needle preparation is obtained.
实施例6硼替佐米原位温敏凝胶的制备Example 6 Preparation of Bortezomib in situ Temperature Sensitive Gel
Figure PCTCN2017116587-appb-000008
Figure PCTCN2017116587-appb-000008
称取处方量的泊洛沙姆407，加入适量的注射用水，低温(4℃)搅拌2小时，直至聚合物分散均匀，于4℃条件保存至凝胶充分溶胀，即凝胶1；将硼替佐米原料药加入至剩余的注射用水中，涡旋2min，超声5min，搅拌1小时，使其分散均匀；将其在低温条件(4℃)缓慢加入至凝胶1中，边加边搅拌，直至呈现均匀的状态，即得硼替佐米温敏凝胶制剂。Weigh the prescribed amount of poloxamer 407, add appropriate amount of water for injection, stir at low temperature (4 ° C) for 2 hours until the polymer is evenly dispersed, and store at 4 ° C until the gel is fully swelled, ie, gel 1; The ezomib was added to the remaining water for injection, vortexed for 2 min, sonicated for 5 min, and stirred for 1 hour to make it evenly dispersed; it was slowly added to the gel 1 under low temperature conditions (4 ° C), and stirred while stirring. Until a uniform state is obtained, a bortezomib temperature sensitive gel formulation is obtained.
释放度实验：Release test:
取硼替佐米原位温敏凝胶置于试管中，于恒温振荡仪37℃下形成凝胶，10min后加入生理盐水，随后将装有凝胶的试管放置恒温振荡仪中，将温度控制在37.0℃±0.5℃，转速为100rpm。整个溶出的过程将试管密封，以防止水分蒸发而影响实验结果。在设定的时间点取样，取样量3mL，同时补充3mL恒温的生理盐水介质，取出的释放液经10000rpm离心5min后，精密量取上清液20μl，注入液相色谱仪，记录色谱图，计算释放百分率，并绘制释放曲线，结果见图4。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 20μl 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.
图4结果显示：实施例6的温敏凝胶制剂在12小时释放约为11％，24小时释放约为19％，96小时释放为45％左右，144小时释放62％左右，持续释放时间达到6天以上。The results in Figure 4 show that the temperature-sensitive gel preparation of Example 6 released about 11% at 12 hours, about 19% at 24 hours, about 45% at 96 hours, about 62% at 144 hours, and lasted for 6 days. the above.
对比实施例1硼替佐米速释制剂Comparative Example 1 Bortezomib immediate release preparation
硼替佐米冻干粉针剂：(1)称取200mg硼替佐米至装有叔丁醇的玻璃瓶中，涡旋并超声，使其充分溶解，得到溶液1；(2)将200mg甘露醇加入至100ml注射用水中，搅拌溶解，加入0.3％(w/v)针用活性炭，80℃搅拌10min，过滤除碳，得到溶液2，备用；(3)将溶液1和溶液2混合，过微孔滤膜除菌，并补加注射用水至200ml；(4)测定含量，灌装，冻干，得到冻干粉针剂。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.
实验实施例1 Experimental Example 1
3.5mg当量的对比实施例1的硼替佐米速释制剂给药空腹比格犬(n＝3)，3.5mg当量的实施例1的硼替佐米原位凝胶注射液，前肢内侧腋窝部位皮下给药，在预定时间点取血，血样在4℃条件下，以4000rpm的转速，离心10min，取上层血浆，用于LC-MS的血药浓度检测，结果见图5。3.5 mg equivalent of the bortezomib immediate release formulation of Comparative Example 1 was administered to an empty beagle dog (n=3), 3.5 mg equivalent of the bortezomib in situ gel injection of Example 1, subcutaneously in the medial axillary region of the forelimb The medicine was taken at a predetermined time point, and the blood sample was centrifuged at 4000 rpm for 10 min at 4 ° C, and the upper layer plasma was taken for LC-MS blood concentration detection. The results are shown in Fig. 5.
相对于粉针剂的Cmax(501.3ng/mL)，原位凝胶制剂提供的血药浓度的Cmax降低至25ng/mL。由药时曲线图5结果可见，相对于速释制剂，原位凝胶制剂亦可快速到达蛋白酶体抑制所需血药浓度，并且血药浓度峰值显著降低，维持时间显著延长，可长期的维持在有效血药浓度范围内，避免了血药浓度峰值过高，可降低药物毒副作用，同时，更好的发挥酶抑制作用和抗肿瘤效果，也为药物剂量爬坡和最佳药效的发挥提供了更大的空间。 C max relative to the powder (501.3ng / mL), plasma concentration C max situ gel formulation provides reduced to 25ng / mL. From the results of the drug time curve 5, it can be seen that compared with the immediate release preparation, 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. In the range of effective blood drug concentration, 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.

Claims (12)

  1. 硼替佐米药物组合物，包含0.1-200重量份，优选0.5-200重量份的活性成分硼替佐米；0.1-500重量份，优选0.5-500重量份的释放速率调节用辅料；0-1000重量份，优选0.1-300重量份，更优选0.1-100重量份，更优选0.1-10重量份的小分子调节剂；和0-2000重量份，优选0.1-2000重量份的药用可注射溶剂。Bortezomib pharmaceutical composition comprising 0.1-200 parts by weight, preferably 0.5-200 parts by weight of active ingredient bortezomib; 0.1-500 parts by weight, preferably 0.5-500 parts by weight of release rate adjusting excipient; 0-1000 weight The fraction is 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 small molecule modifier; and 0 to 2000 parts by weight, preferably 0.1 to 2000 parts by weight, of the pharmaceutically acceptable injectable solvent.
  2. 根据权利要求1所述的硼替佐米药物组合物，其中，The bortezomib pharmaceutical composition according to claim 1, wherein
    所述释放速率调节用辅料为选自可实现局部注射缓释效果的药用辅料，优选选自药用可生物降解的局部注射储库型控释材料、药用油脂、药用表面活性剂的一种或两种以上的组合；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 local injection reservoir type controlled release materials, medicinal oils, and pharmaceutically acceptable surfactants. One or a combination of two or more;
    优选地，所述药用可生物降解的局部注射储库型控释材料为选自：醋酸异丁酸蔗糖酯(SAIB)、聚乳酸(PLA)、聚乳酸-羟基乙酸共聚物(PLGA)、聚乙二醇化的PLA/PLGA、PLGA-PEG-PLGA共聚物、聚原酸酯类、聚磷酸酯共聚物、脂肪酸甘油酯、三乙二醇聚(原酸酯)聚合物、壳聚糖、水溶性羧甲基壳聚糖、丝心蛋白、聚-β-羟基丁酸戊酸酯、聚丙交酯/丙交酯-聚乙二醇共聚物和/或其共混物、聚己内酯-聚乙二醇共聚物、聚β-羟基丁酸酯与聚乙二醇共混物和聚乳酸/羟乙酸共混物中的一种或两种以上的组合；Preferably, the pharmaceutically biodegradable local injection reservoir 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 copolymers, fatty acid glycerides, triethylene glycol poly(orthoester) polymers, chitosan, Water-soluble carboxymethyl chitosan, fibroin, poly-β-hydroxybutyrate valerate, polylactide/lactide-polyethylene glycol copolymer and/or blend thereof, polycaprolactone a combination of one or more of a polyethylene glycol copolymer, a poly-β-hydroxybutyrate and a polyethylene glycol blend and a polylactic acid/glycolic acid blend;
    优选地，所述药用表面活性剂为选自：注射用磷脂、Solutol HS 15、聚山梨醇酯、聚氧乙烯蓖麻油、聚氧乙烯脂肪酸酯、泊洛沙姆、磷脂酰胆碱(如DEPC或DOPC或它们的组合物)、磷脂酰甘油(如DPPG)、聚乙二醇、单硬脂酸甘油酯、明胶中的一种或两种以上的组合；Preferably, the pharmaceutically acceptable surfactant is selected from the group consisting of phospholipids for injection, Solutol HS 15, polysorbate, polyoxyethylene castor oil, polyoxyethylene fatty acid ester, poloxamer, phosphatidylcholine ( Such as DEPC or DOPC or a combination thereof), phosphatidylglycerol (such as DPPG), polyethylene glycol, glyceryl monostearate, gelatin or a combination of two or more;
    优选地，所述药用油脂为选自：甘油、胆固醇、丙二醇酯、乙二醇酯、角鲨烯、硬脂酸、橄榄油、大豆油、椰子油、蓖麻油、芝麻油、玉米油、花生油、棉籽油、茶油、鱼油、甘油三脂(如油酸甘油三酯或辛酸甘油三酯)、甘油油酸或其与磷脂的混合物以及相应盐中的一种或两种以上的组合；Preferably, the medicinal oil or fat is selected from the group consisting of glycerin, cholesterol, propylene glycol ester, ethylene glycol ester, squalene, stearic acid, olive oil, soybean oil, coconut oil, castor oil, sesame oil, corn oil, peanut oil a combination of cottonseed oil, tea oil, fish oil, triglyceride (such as oleic acid triglyceride or caprylic triglyceride), glycerol oleic acid or a mixture thereof with phospholipids, and a corresponding salt;
    其中，所述小分子调节剂为选自：乙酸、无水枸橼酸、抗坏血酸、氯化钙、苯甲酚、依地酸钙二钠、依地酸钠、甘氨酸、组氨酸、赖氨酸、盐酸、乳酸、单水乳糖、氯化镁、甘露醇、甲磺酸、蛋氨酸、苯酚、磷酸、无水磷酸氢二钾、醋酸钠、抗坏血酸钠、碳酸氢钠、亚硫酸氢钠、氯化钠、柠檬酸钠、氢氧化钠、磷酸钠、磷酸氢二钠、磷酸二氢钠、磷酸钾、磷酸氢二钾、磷酸二氢钾、碳酸钠、碳酸氢钠、葡甲胺、鱼精蛋白、对羟基苯甲酸丙酯、胆固醇、植物甾醇、精氨酸、三乙醇胺、葡萄糖、山梨醇、蔗糖、酒石酸、氨丁三醇、醋酸锌、氯化锌、葡萄糖中的一种或两种以上的组合；和/或 Wherein, 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, glucose, sorbitol, sucrose, tartaric acid, tromethamine, zinc acetate, zinc chloride, and glucose Combination; and/or
    所述药用可注射溶剂为水、苯甲醇、氯丁醇、二甲亚砜、甲基吡咯烷酮、二甲基乙酰胺、丙二醇、聚乙二醇、聚乙二醇(单)甲醚、三乙酸甘油酯、苯甲酸苄酯、油酸乙酯、甘油糖醛、甘油缩甲醛、丙二醇、乙醇、乙二醇二***中的一种或两种以上的组合。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, ethyl oleate, glycerol aldehyde, glycerol formal, propylene glycol, ethanol, ethylene glycol diethyl ether.
  3. 根据权利要求1或2所述的硼替佐米药物组合物，其中，所述硼替佐米药物组合物在给药后，在水性介质中，37℃条件下，6小时内释放量小于硼替佐米总量的20％，甚至可小于10％；24h释放量小于硼替佐米总量的40％，甚至可小于30％；90％药物释放时间>3天，甚至可大于7天，大于10天或大于15天。The bortezomib pharmaceutical composition according to claim 1 or 2, wherein the bortezomib pharmaceutical composition is released in an aqueous medium at 37 ° C for 6 hours less than bortezomib after administration. 20% of the total, even less than 10%; 24h release is less than 40% of the total amount of bortezomib, or even less than 30%; 90% drug release time > 3 days, even more than 7 days, more than 10 days or More than 15 days.
  4. 根据权利要求1至3中任一项所述的硼替佐米药物组合物，其中，所述硼替佐米药物组合物在给药后，通过可控的释放行为可调节药物的吸收行为，维持有效抑制蛋白酶体所需的血药浓度至几天，甚至十几天，例如该有效血药浓度可几天至十几天维持在1ng/mL以上，但浓度小于200ng/ml，甚至小于100ng/ml，甚至小于50ng/ml，即维持血药浓度几天至十几天地处于80％蛋白酶体抑制水平，进而维持在有效的蛋白酶体抑制水平数天，甚至十数天，增加药物抗肿瘤疗效。The bortezomib pharmaceutical composition according to any one of claims 1 to 3, wherein the bortezomib pharmaceutical composition maintains an effective absorption behavior of the drug by a controlled release behavior after administration, and remains effective The blood concentration required to inhibit the proteasome is up to several days, even ten days. For example, the effective blood concentration can be maintained above 1 ng/mL for several days to ten days, but the concentration is less than 200 ng/ml, or even less than 100 ng/ml. Even less than 50 ng/ml, that is, maintaining the blood drug concentration at 80% proteasome inhibition level for several days to ten days, and then maintaining the effective proteasome inhibition level for several days, even ten days, increasing the anti-tumor effect of the drug.
  5. 根据权利要求1至4中任一项所述的硼替佐米药物组合物，其中，所述硼替佐米药物组合物选自供注射或埋植用的混悬剂、油针制剂、缓释微球、植入凝胶、多囊脂质体、SABER delivery system和Camurus FluidCrystal injection***。The bortezomib pharmaceutical composition according to any one of claims 1 to 4, wherein the bortezomib pharmaceutical composition is selected from the group consisting of a suspension for injection or implantation, an oil needle preparation, and a sustained release micro Balls, implanted gels, multivesicular liposomes, SABER delivery systems and Camurus FluidCrystal injection systems.
  6. 根据权利要求1至4中任一项所述的硼替佐米药物组合物，其中，The bortezomib pharmaceutical composition according to any one of claims 1 to 4, wherein
    所述硼替佐米药物组合物为硼替佐米多囊脂质体，The bortezomib pharmaceutical composition is bortezomib polycapsule liposome,
    优选地，所述硼替佐米多囊脂质体包含0.1-200重量份，优选0.5-100重量份，更优选1-50重量份的硼替佐米；0.1-300重量份、优选0.1-200重量份的脂质成分，和非必须的0-1000重量份，优选0.1-300重量份，更优选0.1-100重量份，更优选0.1-10重量份的脂质膜流动性调节剂/pH/渗透压调节剂；Preferably, the bortezomib polycapsule liposome comprises 0.1 to 200 parts by weight, preferably 0.5 to 100 parts by weight, more preferably 1 to 50 parts by weight of bortezomib; 0.1 to 300 parts by weight, preferably 0.1 to 200 parts by weight Parts of the lipid component, and optionally 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 the lipid membrane fluidity regulator / pH / penetration Pressure regulator
    优选地，所述硼替佐米多囊脂质体包括未被多囊脂质体包裹的游离硼替佐米，未被多囊脂质体装载的游离硼替佐米的量一般小于组合物中硼替佐米总量的20％，优选小于10％；Preferably, the bortezomib multivesicular liposome comprises free bortezomib not encapsulated by polycystic liposomes, and the amount of free bortezomib not loaded with polyvesicular liposomes is generally less than the amount of bortezomib in the composition 20% of the total amount of rice, preferably less than 10%;
    优选地，所述脂质成分为至少一种两亲性脂质和/或至少一种中性脂质；Preferably, the lipid component is at least one amphiphilic lipid and / or at least one neutral lipid;
    优选地，所述两亲性脂质为磷脂酰胆碱、磷脂酰甘油、相应盐或以上两种以上成分的组合；Preferably, the amphiphilic lipid is phosphatidylcholine, phosphatidylglycerol, a corresponding salt or a combination of two or more of the above;
    优选地，磷脂酰甘油是二棕榈酰磷脂酰甘油(DPPG)，磷脂酰胆碱为二芥酰基卵磷脂(DEPC)或二油酰磷脂酰胆碱(DOPC)或它们的组合物； Preferably, the phosphatidylglycerol is dipalmitoylphosphatidylglycerol (DPPG), the phosphatidylcholine is di-erucyl lecithin (DEPC) or dioleoylphosphatidylcholine (DOPC) or a combination thereof;
    优选地，所述中性脂质为选自乙二醇酯、角鲨烯、甘油、甘油三脂和丙二醇酯的一种或两种以上的组合；Preferably, the neutral lipid is one or a combination of two or more selected from the group consisting of ethylene glycol ester, squalene, glycerin, triglyceride and propylene glycol ester;
    优选地，甘油三脂选自油酸甘油三酯或辛酸甘油三酯；Preferably, the triglyceride is selected from the group consisting of oleic acid triglyceride or caprylic triglyceride;
    优选地，所述脂质膜流动性调节剂选自胆固醇和植物甾醇；Preferably, the lipid membrane fluidity regulator is selected from the group consisting of cholesterol and phytosterols;
    所述pH调节剂为选自非有机酸、有机酸、非有机碱、有机碱中的一种或两种以上的组合，例如，pH调节剂为选自盐酸、磷酸、酒石酸、组氨酸、赖氨酸、丁氨酸、氨丁三醇中的一种或两种以上的组合；The pH adjuster 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. For example, the pH adjuster is selected from the group consisting of hydrochloric acid, phosphoric acid, tartaric acid, and histidine. One or a combination of two or more of lysine, butyrine, and tromethamine;
    优选地，所述渗透压调节剂选自氯化钠、葡糖糖、蔗糖和甘露醇中的一种或两种以上的组合；优选地，所述多囊脂质体的外相水溶液pH范围可在4.0-9.0之间；Preferably, the osmotic pressure adjusting agent is selected from one or a combination of two or more of sodium chloride, glucose sugar, sucrose, and mannitol; preferably, the outer phase aqueous solution pH range of the multi-vesicle liposome is Between 4.0 and 9.0;
    优选地，所述硼替佐米多囊脂质体优选通过静脉、皮下或肌肉注射给药，更优选皮下注射给药；Preferably, the bortezomib multivesicular liposome is preferably administered by intravenous, subcutaneous or intramuscular injection, more preferably subcutaneous injection;
    优选地，所述硼替佐米多囊脂质体于6小时内释放量小于制剂中硼替佐米总量的20％，优选小于10％，甚至小于5％；24h释放量小于硼替佐米总量的40％，优选小于30％，甚至小于20％；90％药物释放时间>3天。Preferably, the release amount of the bortezomib vesicle liposome in 6 hours is less than 20%, preferably less than 10%, or even less than 5% of the total amount of bortezomib in the preparation; the release amount of 24h is less than the total amount of bortezomib 40%, preferably less than 30%, or even less than 20%; 90% drug release time > 3 days.
  7. 根据权利要求1至4中任一项所述的硼替佐米药物组合物，其中，The bortezomib pharmaceutical composition according to any one of claims 1 to 4, wherein
    所述硼替佐米药物组合物为硼替佐米混悬剂，The bortezomib pharmaceutical composition is a bortezomib suspension,
    优选地，所述硼替佐米混悬剂包含0.1-200重量份，优选0.5-100重量份，更优选1-50重量份，更优选1-20重量份的硼替佐米；0-2000重量份，优选0-300重量份，更优选0.5-300重量份的药用可注射溶剂；0.1-500重量份，优选0.5-500重量份的释放速率调节用辅料；0-1000重量份，优选0.1-300重量份，更优选0.1-100重量份，更优选0.1-5重量份的等渗剂和/或缓冲剂；Preferably, the bortezomib suspension comprises 0.1-200 parts by weight, preferably 0.5-100 parts by weight, more preferably 1-50 parts by weight, more preferably 1-20 parts by weight of 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, preferably 0.1- 300 parts by weight, more preferably 0.1 to 100 parts by weight, still more preferably 0.1 to 5 parts by weight, of an isotonic agent and/or a buffering agent;
    优选地，所述释放速率调节用辅料选自药用油脂、表面活性剂和聚合物，例如，所述表面活性剂为选自注射用磷脂、聚山梨醇酯80、聚山梨醇酯20、聚氧乙烯蓖麻油50、聚氧乙烯蓖麻油60、泊洛沙姆和聚氧乙烯脂肪酸酯中的一种或两种以上的组合；Preferably, the release rate adjusting excipient is selected from the group consisting of medicinal oils and fats, surfactants and polymers, for example, the surfactant is selected from the group consisting of phospholipids for injection, polysorbate 80, polysorbate 20, and poly One or a combination of two or more of oxyethylene castor oil 50, polyoxyethylene castor oil 60, poloxamer and polyoxyethylene fatty acid ester;
    所述药用油脂为选自：椰子油、蓖麻油、芝麻油、玉米油、大豆油、花生油、棉籽油、茶油、鱼油、甘油、胆固醇、丙二醇酯、乙二醇酯、角鲨烯、硬脂酸、甘油三脂(如油酸甘油三酯或辛酸甘油三酯)、甘油油酸或其与磷脂的混合物以及相应盐中的一种或两种以上的组合；The medicinal oil is selected from the group consisting of coconut oil, castor oil, sesame oil, corn oil, soybean oil, peanut oil, cottonseed oil, tea oil, fish oil, glycerin, cholesterol, propylene glycol ester, ethylene glycol ester, squalene, hard a combination of fatty acid, triglyceride (such as oleic acid triglyceride or caprylic triglyceride), glycerol oleic acid or a mixture thereof with a phospholipid, and one or more of the corresponding salts;
    所述聚合物为选自羧甲基纤维素钠、醋酸乙烯酯共聚物、泊洛沙姆、聚乙二醇、羟基乳酸聚合物、聚酯、聚多糖和聚维酮K12/K17中的一种或两种以上的组合； The polymer is one selected from the group consisting of sodium carboxymethyl cellulose, vinyl acetate copolymer, poloxamer, polyethylene glycol, hydroxylactic acid polymer, polyester, polypolysaccharide and povidone K12/K17. Species or a combination of two or more;
    优选地，所述缓冲剂为选自磷酸钠、磷酸氢二钠、磷酸二氢钠、磷酸钾、磷酸氢二钾、磷酸二氢钾、柠檬酸钠、碳酸钠、碳酸氢钠、葡甲胺、精氨酸、三乙醇胺和枸橼酸中的一种或两种以上的组合；Preferably, the buffer is selected from the group consisting of sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, sodium citrate, sodium carbonate, sodium hydrogencarbonate, meglumine. , one or a combination of two or more of arginine, triethanolamine, and citric acid;
    优选地，所述药用可注射溶剂为选自：水、苯甲醇、氯丁醇、二甲亚砜、甲基吡咯烷酮、二甲基乙酰胺、丙二醇、聚乙二醇、聚乙二醇(单)甲醚、三乙酸甘油酯、苯甲酸苄酯、油酸乙酯、甘油糖醛、甘油缩甲醛、丙二醇、乙醇、乙二醇二***中的一种或两种以上的组合；Preferably, the pharmaceutically acceptable 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) one or a combination of two or more of methyl ether, triacetin, benzyl benzoate, ethyl oleate, glycerol aldehyde, glycerol formal, propylene glycol, ethanol, ethylene glycol diethyl ether;
    优选地，所述等渗剂为选自氯化钠、蔗糖、葡糖糖和甘露醇中的一种或两种以上的组合；Preferably, the isotonic agent is one or a combination of two or more selected from the group consisting of sodium chloride, sucrose, glucose, and mannitol;
    优选地，所述硼替佐米混悬剂是纳米混悬剂或微米混悬剂，纳米混悬剂粒径范围优选是50-800nm，微米混悬剂的粒径范围优选是1-18μm。Preferably, the bortezomib suspension is a nanosuspension or a microsuspension, the nanosuspension preferably has a particle size ranging from 50 to 800 nm, and the microsuspension preferably has a particle size ranging from 1 to 18 μm.
  8. 根据权利要求1至4中任一项所述的硼替佐米药物组合物，其中，The bortezomib pharmaceutical composition according to any one of claims 1 to 4, wherein
    所述硼替佐米药物组合物为硼替佐米原位凝胶***，The bortezomib pharmaceutical composition is a bortezomib in situ gel system,
    优选地，所述硼替佐米原位凝胶***包含0.1-200重量份，优选0.5-100重量份，更优选1-50重量份，甚至更优选1-20重量份的硼替佐米；0.1-2000重量份，优选50-2000重量份，更优选100-1000重量份的溶剂；0.1-500重量份，优选0.5-250重量份，更优选1-100重量份，甚至更优选2-50重量份的释放速率调节用凝胶形成材料；Preferably, the bortezomib in situ gel system comprises 0.1 to 200 parts by weight, preferably 0.5 to 100 parts by weight, more preferably 1 to 50 parts by weight, even more preferably 1 to 20 parts by weight of bortezomib; 0.1 to 2000 Part by weight, preferably 50-2000 parts by weight, more preferably 100-1000 parts by weight of the solvent; 0.1-500 parts by weight, preferably 0.5-250 parts by weight, more preferably 1-100 parts by weight, even more preferably 2-50 parts by weight Release rate adjusting gel forming material;
    优选地，所述溶剂为选自N-甲基吡咯烷酮、聚乙二醇(单)甲醚、三乙酸甘油酯、苯甲酸苄酯、甘油糖醛、甘油缩甲醛、丙二醇、乙醇、乙二醇二***、苯甲醇、二甲亚砜中的一种或两种以上的组合；Preferably, the solvent is selected from the group consisting of N-methylpyrrolidone, polyethylene glycol (mono) methyl ether, triacetin, benzyl benzoate, glycerol aldehyde, glycerol formal, propylene glycol, ethanol, ethylene glycol One or a combination of two or more of diethyl ether, benzyl alcohol, and dimethyl sulfoxide;
    优选地，所述释放速率调节用凝胶形成材料为选自：聚乳酸(PLA)、聚乳酸-羟基乙酸共聚物(PLGA)、聚原酸酯、醋酸异丁酸蔗糖酯、脂肪酸甘油酯、聚乙二醇化的PLA/PLGA、PLGA-PEG-PLGA共聚物、聚己内酯-聚乙二醇共聚物、三乙二醇聚(原酸酯)聚合物、泊洛沙姆中的一种或两种以上的组合；Preferably, the gel forming material for release rate adjustment is selected from the group consisting of polylactic acid (PLA), polylactic acid-glycolic acid copolymer (PLGA), polyorthoester, sucrose acetate isobutyrate, fatty acid glyceride, Pegylated PLA/PLGA, PLGA-PEG-PLGA copolymer, polycaprolactone-polyethylene glycol copolymer, triethylene glycol poly(orthoester) polymer, one of poloxamers Or a combination of two or more;
    优选地，所述原位凝胶***中的硼替佐米的单次给药量范围是0.1-200mg，优选0.5-100mg，更优选1-50mg，甚至更优选2-25mg；Preferably, the single dose of 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 2 to 25 mg;
    优选地，所述硼替佐米原位凝胶***，于6小时内释放量小于制剂中硼替佐米总量的20％，优选小于10％，甚至小于5％；24h释放量小于硼替佐米总量的40％，甚至小于30％；90％药物释放时间>3天； Preferably, the bortezomib in situ gel system releases less than 20%, preferably less than 10%, or even less than 5% of the total amount of bortezomib in the formulation within 6 hours; the release amount of 24h is less than the total amount of bortezomib 40%, even less than 30%; 90% drug release time > 3 days;
    优选地，所述原位凝胶***以溶液状态短期贮存，或以预分装药物和溶剂的注射器形式贮存；Preferably, the in situ gel system is stored for short periods in a solution state or in the form of a syringe prepackaged with a drug and a solvent;
    优选地，所述原位凝胶***通过静脉、皮下或肌肉注射给药，优选皮下和肌肉注射给药。Preferably, the in situ gel system is administered by intravenous, subcutaneous or intramuscular injection, preferably subcutaneously and intramuscularly.
  9. 根据权利要求1至4中任一项所述的硼替佐米药物组合物，其中，The bortezomib pharmaceutical composition according to any one of claims 1 to 4, wherein
    所述硼替佐米药物组合物为缓释微球，The bortezomib pharmaceutical composition is a sustained release microsphere,
    优选地，所述缓释微球包含0.1-200重量份，优选0.5-100重量份，甚至更优选1-50重量份，甚至更优选1-20重量份的硼替佐米，和0.1-500重量份，优选0.2-250重量份，甚至更优选1-200重量份的释放速率调节用聚合物；Preferably, the sustained release microspheres comprise 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 bortezomib, and 0.1 to 500 parts by weight. Parts, 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;
    优选地，所述缓释微球为干燥粉末，临用前，需用可注射用水或其他溶剂混悬均匀后注射；所述其他溶剂为不影响微球稳定性的注射用溶剂，优选选自甘油、聚乙二醇、0.1wt％-1wt％聚山梨醇酯80的水溶液中的一种或两种以上组合；Preferably, the sustained release microspheres are dry powders, and are sprayed uniformly with water for injection or other solvents before use; the other solvents are injection solvents which do not affect the stability of the microspheres, preferably selected from the group consisting of One or a combination of two or more of an aqueous solution of glycerin, polyethylene glycol, 0.1% by weight to 1% by weight of polysorbate 80;
    优选地，所述缓释微球粒径分布在0.5～20μm之间；Preferably, the sustained release microspheres have a particle size distribution between 0.5 and 20 μm;
    优选地，所述释放速率调节用聚合物为选自聚乳酸(PLA)、聚乳酸-羟基乙酸共聚物(PLGA)、聚乙二醇化的PLA/PLGA、壳聚糖、水溶性羧甲基壳聚糖、丝心蛋白、聚-β-羟基丁酸戊酸酯、聚丙交酯/丙交酯-聚乙二醇共聚物共混物、聚β-羟基丁酸酯与聚乙二醇共混物、聚乳酸/羟乙酸共混物中的一种或两种以上组合；Preferably, the release rate adjusting polymer is selected from the group consisting of polylactic acid (PLA), polylactic acid-glycolic acid copolymer (PLGA), pegylated PLA/PLGA, chitosan, water-soluble carboxymethyl shell Glycan, fibroin, poly-β-hydroxybutyrate valerate, polylactide/lactide-polyethylene glycol copolymer blend, poly-β-hydroxybutyrate and polyethylene glycol blend One or a combination of two or more of the polylactic acid/glycolic acid blends;
    优选地，所述缓释微球通过静脉、皮下或肌肉注射给药，优选皮下和肌肉注射给药。Preferably, the sustained release microspheres are administered by intravenous, subcutaneous or intramuscular injection, preferably subcutaneously and intramuscularly.
  10. 根据权利要求1至4中任一项所述的硼替佐米药物组合物，其中，The bortezomib pharmaceutical composition according to any one of claims 1 to 4, wherein
    所述硼替佐米药物组合物为硼替佐米油针注射剂，The bortezomib pharmaceutical composition is a bortezomib oil injection,
    优选地，所述硼替佐米油针制剂包含0.1-200重量份，优选0.5-100重量份，更优选1-50重量份，更优选1-20重量份的硼替佐米；0.1-500重量份，优选0.5-500重量份的释放速率调节用辅料；0-300重量份，优选0-100重量份，更优选0.1-100重量份的药用可注射溶剂；0-1000重量份，优选0.1-300重量份，更优选0.1-100重量份，更优选0.1-10重量份的小分子调节剂；Preferably, the bortezomib oil needle preparation comprises 0.1 to 200 parts by weight, preferably 0.5 to 100 parts by weight, more preferably 1 to 50 parts by weight, more preferably 1 to 20 parts by weight of bortezomib; 0.1 to 500 parts by weight Preferably, 0.5 to 500 parts by weight of the release rate adjusting adjuvant; 0 to 300 parts by weight, preferably 0 to 100 parts by weight, more preferably 0.1 to 100 parts by weight of the 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;
    优选地，所述释放速率调节用辅料为选自药用油脂、表面活性剂或聚合物，例如，所述表面活性剂为选自注射用磷脂、聚山梨醇酯80、聚山梨醇酯20、聚氧乙烯蓖麻油50、聚氧乙烯蓖麻油60、泊洛沙姆和聚氧乙烯脂肪酸酯中的一种或两种以上组合；所用药用油脂为选自：甘油、胆固醇、丙二醇酯、乙二醇酯、角鲨烯、硬脂酸、橄榄油、大豆油、椰子油、蓖麻油、芝麻油、玉米油、花生油、棉籽油、茶油、鱼油、甘油三脂(如油酸甘油三酯或辛酸甘油三酯)、甘油油酸或其与磷脂的混合物以及相应盐中的一种或两种以上的组合；所述聚合物为选自羧甲基纤维素钠、醋酸乙烯酯共聚物、泊洛沙 姆、聚乙二醇、羟基乳酸聚合物、聚酯、聚多糖和聚维酮K12/K17中的一种或两种以上的组合；Preferably, the release rate adjusting excipient is selected from the group consisting of medicinal oils and fats, surfactants or polymers, for example, the surfactant is selected from the group consisting of phospholipids for injection, polysorbate 80, polysorbate 20, One or a combination of polyoxyethylene castor oil 50, polyoxyethylene castor oil 60, poloxamer and polyoxyethylene fatty acid ester; the medicinal oil and fat used is selected from the group consisting of glycerin, cholesterol, propylene glycol ester, Ethylene glycol ester, squalene, stearic acid, olive oil, soybean oil, coconut oil, castor oil, sesame oil, corn oil, peanut oil, cottonseed oil, tea oil, fish oil, triglyceride (such as oleic acid triglyceride) Or a combination of glyceryl oleate), glycerol oleic acid or a mixture thereof with a phospholipid, and one or more of the corresponding salts; the polymer is selected from the group consisting of sodium carboxymethyl cellulose, a copolymer of vinyl acetate, Polosa a combination of one or more of dimethyl, polyethylene glycol, hydroxylactic acid polymer, polyester, polysaccharide, and povidone K12/K17;
    优选地，所述药用可注射溶剂为选自苯甲醇、氯丁醇、二甲亚砜、甲基吡咯烷酮、二甲基乙酰胺、丙二醇、聚乙二醇、聚乙二醇(单)甲醚、三乙酸甘油酯、苯甲酸苄酯、油酸乙酯、甘油糖醛、甘油缩甲醛、丙二醇、乙醇、乙二醇二***中的一种或两种以上的组合；Preferably, the pharmaceutically acceptable injectable solvent is selected from the group consisting of benzyl alcohol, chlorobutanol, dimethyl sulfoxide, methyl pyrrolidone, dimethyl acetamide, propylene glycol, polyethylene glycol, polyethylene glycol (single) A One or a combination of two or more of ether, triacetin, benzyl benzoate, ethyl oleate, glycerol aldehyde, glycerol formal, propylene glycol, ethanol, ethylene glycol diethyl ether;
    优选地，所述小分子调节剂为选自磷酸钠、磷酸氢二钠、磷酸二氢钠、柠檬酸钠、磷酸钾、磷酸氢二钾、磷酸二氢钾、碳酸钠、碳酸氢钠、葡甲胺、精氨酸、三乙醇胺、枸橼酸、氯化钠、葡糖糖、蔗糖和甘露醇中的一种或两种以上的组合。Preferably, 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, and hydrochloric acid. One or a combination of two or more of methylamine, arginine, triethanolamine, citric acid, sodium chloride, glucose, sucrose, and mannitol.
  11. 根据权利要求1至10中任一项所述的硼替佐米药物组合物在制备用于治疗和/或预防多发性骨髓瘤的药物中的用途。Use of a bortezomib pharmaceutical composition according to any one of claims 1 to 10 for the manufacture of a medicament for the treatment and/or prevention of multiple myeloma.
  12. 根据权利要求11所述的用途，其中硼替佐米药物组合物单次给药量范围是0.1-200mg活性药物，优选0.5-100mg活性药物，更优选1-50mg活性药物，甚至更优选1-20mg活性药物。 The use according to claim 11, wherein the bortezomib pharmaceutical composition is administered in a single dose in the range of 0.1 to 200 mg of the active drug, preferably 0.5 to 100 mg of the active drug, more preferably 1 to 50 mg of the active drug, even more preferably 1 to 20 mg Active drug.
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