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WO2018108163A1 - Composition pharmaceutique de talazoparib et ses applications - Google Patents

Composition pharmaceutique de talazoparib et ses applications Download PDF

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Publication number
WO2018108163A1
WO2018108163A1 PCT/CN2017/116573 CN2017116573W WO2018108163A1 WO 2018108163 A1 WO2018108163 A1 WO 2018108163A1 CN 2017116573 W CN2017116573 W CN 2017116573W WO 2018108163 A1 WO2018108163 A1 WO 2018108163A1
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Prior art keywords
talazoparib
parts
weight
acid
oil
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PCT/CN2017/116573
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English (en)
Chinese (zh)
Inventor
甘勇
朱全垒
郭仕艳
朱春柳
张馨欣
宋文艺
Original Assignee
中国科学院上海药物研究所
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Priority to CN201780011152.3A priority Critical patent/CN110035743B/zh
Publication of WO2018108163A1 publication Critical patent/WO2018108163A1/fr

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    • 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—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • 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
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • 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
    • A61K9/14—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
    • 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 PARP enzyme inhibitor Talazoparib pharmaceutical composition for tumor application and its use for treating cancer, the pharmaceutical composition having a controlled release behavior capable of being maintained Stable in vivo blood concentration and long-acting PARP enzyme inhibitory activity.
  • PARP polyadenosine diphosphate-ribose polymerase
  • BRCA1 and BRCA2 genes proteins encoded by BRCA1 and BRCA2 genes are involved in the repair of DNA double-strand damage through the homologous recombination (HR) pathway.
  • HR homologous recombination
  • PARP inhibitors such as Talazoparib inhibit PARP activity, resulting in single-strand DNA breakage damage in cells that are not repaired and accumulated, and sustained single-strand DNA damage will be converted into double-stranded DNA damage during DNA replication. Because tumor cells deficient in BRCA1/2 gene function cannot repair double-stranded DNA damage through HR, this will lead to the cessation of DNA replication fork, produce cytotoxicity, lead to synthetic lethality, and ultimately target killing of tumor cells.
  • phase II clinical dose was finally determined to be 1000 ⁇ g/day.
  • the final recommended phase II clinical dose is 1 mg/time/day.
  • the plasma half-life of Talazoparib is longer (>40h, also reported in the data >100 hours), and the steady-state plasma peak and trough concentrations are 50nM (19.02ng). /mL) and 10 nM (3.80 ng/mL).
  • Patent searches have not yet published patents relating to Talazoparib.
  • the present invention discloses a controlled release composition that precisely regulates the level and fluctuation range of Talazoparib blood levels, which controllably regulates the long-term maintenance of blood levels required for enzyme inhibition, At the same time, the fluctuation range of blood drug concentration is lowered, and the PARP enzyme inhibition rate and anti-tumor effect of the tumor cells are improved, and the adverse reactions after the drug administration are reduced, and the compliance of the patients is increased.
  • the primary object of the present invention is to provide a Talazoparib pharmaceutical composition with controlled in vivo absorption behavior, blood concentration and PARP enzyme inhibition level in order to further enhance Talazoparib in view of the biological properties of Talazoparib and the efficacy and safety requirements of clinical treatment.
  • the clinical efficacy reduces the adverse reactions of patients with cancer after medication and increases the compliance of patients taking medication.
  • the present invention relates to a combination of novel drugs with improved Talazoparib drug loading and/or in vivo absorption and/or bioavailability and/or blood drug concentration control and/or enzyme inhibition level control and their combination as a sole formulation or other therapy for cancer treatment the use of.
  • the active ingredient Talazoparib in the Talazoparib pharmaceutical composition provided by the present invention may be a free base form of Talazoparib or a compound in the form of a pharmaceutically acceptable salt thereof, such as Talazoparib tosylate, Talazoparib Hydrochloride, Talazoparib Sulfate, Talazoparib Maleate and Talazoparib Camphorate.
  • the active ingredient Talazoparib in the pharmaceutical composition of the present invention includes the free base of Talazoparib and a pharmaceutically acceptable salt thereof.
  • the present invention provides a Talazoparib pharmaceutical composition
  • a Talazoparib pharmaceutical composition comprising 0.1 to 200 parts by weight, preferably 0.5 to 200 parts by weight, of the active ingredient Talazoparib; 0.1 to 500 parts by weight, preferably 0.5 to 500 parts by weight, for release rate adjustment Excipient; 0-1000 parts by weight, 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, preferably 0.5-2000 parts by weight of medicinal Injectable solvent.
  • the excipient for regulating drug release rate in the composition of the present invention is selected from the group consisting of pharmaceutical excipients which can achieve a sustained injection effect of local injection, preferably selected from the group consisting of pharmaceutically biodegradable polymers, medicinal oils, pharmaceutically acceptable surfactants, etc.
  • the pharmaceutically biodegradable polymer may be selected from the group consisting of polylactic acid (PLA), polylactic acid-glycolic acid copolymer (PLGA), polyorthoesters, acetic acid- Sucrose isobutyrate, fatty acid glyceride, pegylated PLA/PLGA, PLGA-PEG-PLGA copolymer, triethylene glycol poly(orthoester) polymer, chitosan, water-soluble carboxymethyl shell Glycan, fibroin, poly- ⁇ -hydroxybutyrate valerate, polylactide/lactide-polyethylene glycol copolymer or blend thereof, polycaprolactone-polyethylene glycol copolymer, One or a combination of two or more of a poly- ⁇ -hydroxybutyrate and a polyethylene glycol blend and a polylactic acid/glycolic acid blend.
  • PLA polylactic acid
  • PLGA polylactic acid-glycolic acid copolymer
  • the pharmaceutically acceptable surfactant may be selected from the group consisting of phospholipids for injection, Solutol HS15, polysorbate, polyoxyethylene castor oil, poloxamer, polyoxyethylene fatty acid ester, phosphatidylcholine (such as DEPC or One or a combination of two or more of DOPC or a combination thereof, phosphatidylglycerol (such as DPPG), polyethylene glycol, glyceryl monostearate, gelatin.
  • phospholipids for injection Solutol HS15, polysorbate, polyoxyethylene castor oil, poloxamer, polyoxyethylene fatty acid ester, phosphatidylcholine (such as DEPC or One or a combination of two or more of DOPC or a combination thereof, phosphatidylglycerol (such as DPPG), polyethylene glycol, glyceryl monostearate, gelatin.
  • the medicinal oil or fat may be 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, triglycerides (such as oleic acid triglyceride or caprylic triglyceride) and other medicinal oils and fats (such as oleic acid glycerides, such as glycerol monooleate, diolein, three One or a combination of two or more of oleic acid glycerides and mixtures thereof with phospholipids and the like) and corresponding salts.
  • glycerin such as oleic acid triglyceride or caprylic triglyceride
  • other medicinal oils and fats such as oleic acid glycerides, such as glycerol monoole
  • the small molecule regulator may specifically be selected from the group consisting of an osmotic pressure or a pH adjuster, such as acetic acid, anhydrous citric acid, ascorbic acid, calcium chloride, cresol, disodium calcium edetate, Sodium sulphate, glycine, histidine, lysine Acid, hydrochloric acid, lactic acid, lactose monohydrate, magnesium chloride, mannitol, methanesulfonic acid, methionine, phenol, phosphoric acid, dipotassium hydrogenhydride, 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, pair One or a combination of two or more of propy
  • the pharmaceutically injectable solvent may be 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, glycerol aldehyde, glycerol formal, propylene glycol, ethanol, ethylene glycol diethyl ether, and other pharmaceutically acceptable injectable solvents.
  • the pharmaceutical composition provided by the present invention may be in the form of a solution, a suspension, a lyophilized powder or a syringe prefilled with a powder or a solution for injection or implantation in the skin, the skin, the muscles and other parts.
  • the pharmaceutical composition provided by the invention may be selected from suspensions for local injection or implantation, oil needle preparations, sustained release microspheres, implanted gels, multivesicular liposomes and other applicable slow control Release local injection delivery systems (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 1 mL per injection or implant.
  • the Talazoparib pharmaceutical composition provided by the invention has a controlled release behavior, and after the injection or the implantation, the release behavior and the release amount are controlled in a release medium which meets the sump condition within a predetermined period of time.
  • the release amount in 6 hours is less than 20%, preferably less than 10%, or even less than 5% of the total amount of Talazoparib at 37 ° C;
  • the release amount of 24 h is less than 40%, preferably less than 30% of the total amount of Talazoparib, It can even be less than 20%; 90% drug release time > 3 days, even greater than 7 days, greater than 14 days or greater than 30 days.
  • the pharmaceutical composition provided by the invention can quickly achieve the blood concentration level required for effective anti-tumor PARP enzyme inhibition after injection, and can avoid blood medicine. Concentration fluctuations, maintained at effective blood levels for several days, even dozens of days.
  • the effective blood drug concentration can be maintained in the range of 0.2-50 ng/mL for several days to several tens of days, and even the plasma concentration is greater than 2 ng/mL ⁇ C ⁇ 25 ng/mL for more than 7 days.
  • the decrease in blood concentration fluctuation and the long-term and high-efficiency PARP enzyme inhibition effect are expected to improve the anti-tumor effect and reduce the toxicity. It can realize the regulation of the more effective and low-toxicity of tumor patients and the regulation of the frequency of administration.
  • the present invention provides the use of the Talazoparib pharmaceutical composition for the preparation of a medicament for the treatment and/or prevention of a tumor having a tumor such as ovarian cancer, breast cancer, gastric cancer or the like.
  • the Talazoparib pharmaceutical composition provided by the invention can be used for clinical treatment of tumors (such as ovarian cancer, breast cancer, gastric cancer, etc.).
  • tumors such as ovarian cancer, breast cancer, gastric cancer, etc.
  • Controllable release and absorption of the drug can be achieved, providing accurate in vivo blood concentration and long-term stable high-efficiency tumor suppression level, and lasting effect;
  • the effective PARP enzyme inhibition can be maintained for a long time, which reduces the cumbersome process of daily administration of the common preparation, and is more convenient for clinical use;
  • 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 in situ precipitated gel formulation of Example 1 talazoparib.
  • Figure 2 shows the in vitro release profile of Example 2 talazoparib sustained release microspheres.
  • Figure 3 shows the in vitro release profile of Example 3 talazoparib polycystic liposomes.
  • Figure 4 shows the in vitro release profile of the Example 6 talazoparib in situ temperature sensitive gel formulation.
  • Figure 5 shows the release profile of the immediate release talazoparib capsule of Comparative Example 1.
  • Figure 6 is a graph showing the canine drug time of the immediate release talazoparib capsule of Comparative Example 1 and the talazoparib in situ gel 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), the first two of which are concentric lipids.
  • MVL is a non-concentric liposome.
  • MVL is an aggregate of non-concentric lipid bilayer vesicles. It is a novel 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 talazoparib pharmaceutical composition of the present invention may be in the form of a talazoparib polycystic liposome comprising the active ingredient talazoparib, a lipid component (including fats and surfactants), and optionally other One or a combination of two or more of the pharmaceutically acceptable pH/osmotic pressure adjusting agents; wherein the talazoparib polycystic liposome composition comprises 0.1 to 200 parts by weight, preferably 0.5 to 100 parts by weight, more preferably 1 to 1 50 parts by weight, even more preferably 1-20 parts by weight of the active ingredient talazoparib; 0.1-300 parts by weight, preferably 0.1-200 parts by weight, of the lipid component; and optionally 0-1000 parts by weight, preferably 0.1-300 parts by weight Part, more preferably 0.1 to 100 parts by weight, still more preferably 0.1 to 10 parts by weight, of other pharmaceutically acceptable lipid film fluidity regulator/pH/osmotic pressure regulator.
  • the talazoparib is the only active ingredient loaded into the interior of the multivesicular liposome; the formulation composition may comprise free talazoparib not encapsulated by polycystic liposomes, the amount of free talazoparib not loaded by the polycystic liposomes is generally less than the combination 20%, preferably less than 10%, of the total amount of talazoparib.
  • the lipid component is selected from at least one amphiphilic lipid and/or at least one neutral lipid;
  • the amphiphilic lipid comprises phosphatidylcholine or phosphatidylglycerol or a corresponding salt or one or more a combination of two or more components;
  • the phosphatidylglycerol can be DPPG, and in certain instances, the phosphatidylcholine can be selected from DEPC or DOPC or a combination thereof;
  • the neutral lipid includes B The glycol ester, squalene, glycerin, triglyceride and propylene glycol ester or a mixture of the above components, etc., in a specific example, the triglyceride may be selected from the group consisting of oleic acid triglyceride or caprylic acid triglyceride.
  • the composition preferably includes a lipid membrane fluidity modifier, an osmotic pressure regulator, and/or a pH adjuster;
  • the lipid membrane fluidity modifier may be selected from cholesterol or phytosterols;
  • the regulator 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.
  • the pH adjuster is selected from the group consisting of hydrochloric acid, phosphoric acid, tartaric acid, histidine, and lysine.
  • 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 liposomes of the invention may range in pH from 4.0 to 9.0.
  • the single injection dose of the active ingredient talazoparib in the preparation of the multivesicular liposome composition ranges from 0.1 to 200 mg. In some instances, the amount of uncoated free talazoparib is 0-20% of the total amount of talazoparib in the composition. .
  • 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 A volatile organic solvent (usually chloroform or a mixture of chloroform and diethyl ether) forms an oil phase, and a prescribed amount of talazoparib is dissolved in water to form a medicated aqueous solution (first aqueous phase), and then a suitable oil-water volume ratio (volume ratio) a 1:10-12:10, v/v) aqueous solution containing the drug (The first aqueous phase) is mixed with the organic phase of the lipid (oil phase), and a uniform water-in-oil (W/O) type colostrum is prepared by ultrasonic or mechanical shearing at room temperature for a certain period of time; (2) formed by suction W/O colostrum is injected into the second a
  • the organic solvent may be removed by introducing nitrogen gas into the surface or by inserting a nitrogen gas conduit into the bottom of the conical flask; (4) if necessary, it may be replaced by a salt solution suitable for storage and physiologically acceptable salt solution (such as 0.9% sodium chloride solution).
  • a salt solution suitable for storage and physiologically acceptable salt solution such as 0.9% sodium chloride solution.
  • the second aqueous phase is concentrated; (5) the drug content is adjusted and filled according to the content.
  • 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.
  • Talazoparib polycystic 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 Talazoparib in the preparation in 6 hours; the release amount of 24h is less than 40% of the total amount of Talazoparib, preferably less than 30%, even less than 20%; 90% drug release time > 3 days.
  • the pharmaceutical composition provided by the invention can quickly achieve the blood drug concentration level required for effective anti-tumor PARP enzyme 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 0.2-50 ng/mL for several days to several tens of days, and even the plasma concentration is greater than 2 ng/mL ⁇ C ⁇ 25 ng/mL for more than 7 days.
  • talazoparib pharmaceutical compositions can be practiced in the form of a talazoparib suspension to achieve the release behavior described.
  • the suspension may be selected from aqueous vehicle suspensions or oily vehicle suspensions.
  • the Talazoparib suspension comprises the active ingredient talazoparib, an excipient for release rate regulation, a pharmaceutically acceptable injectable solvent, and/or a suspension stabilizer, and/or an isotonicity agent, a buffering agent, and the like;
  • the talazoparib suspension 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 the active ingredient talazoparib; 0 to 2000 parts by weight, Preferably from 0 to 300 parts by weight, more preferably from 0.5 to 300 parts by weight, of the pharmaceutically acceptable injectable solvent; from 0.1 to 500 parts by weight, preferably from 0.5 to 500 parts by weight, of the release rate adjusting adjuvant; from 0 to 1000 parts by weight, preferably from 0.1 to 300 parts by weight It is 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 the buffering agent.
  • the release rate modifying excipient may be selected from the group consisting of medicinal oils, surfactants, or polymers.
  • the medicinal oil and fat 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.
  • the surfactant may include for injection One or a combination of phospholipid, polysorbate 80, polysorbate 20, polyoxyethylene castor oil 50, polyoxyethylene castor oil 60, poloxamer and polyoxyethylene fatty acid ester, polymerization
  • the substance may include one or both of sodium carboxymethyl cellulose, vinyl acetate copolymer, poloxamer, polyethylene glycol, hydroxylactic acid polymer, polyester, polypolysaccharide and povidone K12/K17. The combination above.
  • 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, potassium phosphate, sodium citrate, 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 talazoparib in the suspension provided by the present invention ranges from 0.1 to 200 mg, preferably from 0.5 to 100 mg; the talazoparib suspension provided by the present invention can be administered subcutaneously or intramuscularly, preferably subcutaneously. .
  • In situ gel implantation is a research hotspot in the field of slow-controlled injections in recent years. It dissolves drugs and polymers in a suitable solvent, and is subcutaneously injected. At the site of administration, the polymer coagulates under physiological conditions. A semi-solid or solid drug reservoir is formed. 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 talazoparib pharmaceutical composition provided by the present invention can achieve the release behavior in the form of a talazoparib in situ gel system, characterized in that the in situ gel system comprises the active ingredient drug talazoparib, a suitable solvent, and a release rate regulating coagulation. Glue forming material.
  • the talazoparib 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 talazoparib; 0.1 to 2000 weight Parts, preferably 50-2000 parts by weight, more preferably 100-1000 parts by weight of a pharmaceutically acceptable injectable solvent; 0.1-500 parts by weight, preferably 0.5-250 parts by weight, even more preferably 1-100 parts by weight of said release A gel forming material for rate adjustment.
  • the talazoparib in situ gel system can be prepared in a manner well known in the art. Specifically, for example, a pharmaceutically acceptable polymer polylactic acid or polylactic acid-glycolic acid copolymer can be dissolved in a solvent such as polyethylene glycol methyl ether or N-methylpyrrolidone.
  • a pharmaceutically acceptable polymer polylactic acid or polylactic acid-glycolic acid copolymer can be dissolved in a solvent such as polyethylene glycol methyl ether or N-methylpyrrolidone.
  • the release rate adjusting gel forming material forms a solution which can directly dissolve the active drug talazoparib, or pre-packaged 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.
  • Polylactide/glycolide-polyethylene glycol copolymer and/or blend thereof, poloxamer or polycaprolactone-polyethylene glycol copolymer and other pharmaceutically acceptable additives may also be dissolved in In the water, a temperature-sensitive gel preparation is prepared, mixed with a solution of the active drug or pre-packaged with the active drug before being mixed with the sterile syringe, and then locally injected into the human body to form a gel material to adjust the drug release rate.
  • a suitable solvent 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, glyceryl triacetate benzyl benzoate, glycerol aldehyde, One or a combination of two or more of glycerol formal, propylene glycol, ethanol, ethylene glycol diethyl ether, benzyl alcohol, dimethyl sulfoxide, and other pharmaceutically acceptable organic solvents.
  • the gel forming material for release rate adjustment comprises: polylactic acid (PLA), polylactic acid-glycolic acid copolymer (PLGA), polyorthoester, sucrose acetate isobutyrate, fatty acid glyceride, PEGylation PLA/PLGA, PLGA-PEG-PLGA copolymer, polycaprolactone-polyethylene glycol copolymer, triethylene glycol poly(orthoester) polymer, poloxamer and other pharmaceutically acceptable local injections One or a combination of two or more of the controlled release materials.
  • PLA polylactic acid
  • PLGA polylactic acid-glycolic acid copolymer
  • polyorthoester sucrose acetate isobutyrate
  • fatty acid glyceride PEGylation PLA/PLGA
  • PLGA-PEG-PLGA copolymer polycaprolactone-polyethylene glycol copolymer
  • triethylene glycol poly(orthoester) polymer poloxamer
  • the single dose of the active ingredient talazoparib 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 Talazoparib in situ gel system provided by the present invention releases less than 20% or even less than 15% of the total amount of Talazoparib in the preparation within 6 hours; the release amount in 24 hours is less than 40% or even less than 30% of the total amount of Talazoparib; 90% drug release time > 3 days.
  • the Talazoparib in situ gel system provided by the invention can rapidly achieve the blood concentration level required for effective anti-tumor PARP enzyme inhibition, and can avoid the fluctuation of blood concentration and maintain the effective blood concentration. Days, even dozens of days.
  • the effective blood drug concentration can be maintained in the range of 0.2-50 ng/mL for several days to several tens of days, and even the plasma concentration is greater than 2 ng/mL ⁇ C ⁇ 25 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 solid formed by dissolving or dispersing a drug in a matrix of a sustained-release polymer material, and has a small particle size and belongs 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 pharmaceutical composition of the present invention can be provided in the form of talazoparib microspheres comprising the active ingredient talazoparib and a release rate adjusting polymeric 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 talazoparib, and 0.1 to 500 parts by weight, It is preferably 0.2 to 250 parts by weight, even more preferably 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 glycerin, One or a combination of two or more of polyethylene glycol, 0.1% by weight to 1% by weight of Tween 80 in an aqueous solution.
  • the talazoparib sustained-release microspheres can be prepared in a manner known in the art. Specifically, the active drug talazoparib and the release rate-adjusting polymer material can be dissolved in a suitable solvent and spray dried by an intelligent spray-drying electrostatic collection system.
  • Talazoparib and a suitable release-regulating polymer material such as polylactic acid-glycolic acid copolymer (PLGA)
  • a solvent such as dichloromethane
  • PLGA polylactic acid-glycolic acid copolymer
  • 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 the amount of ventilation, 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 amount, etc.
  • the physicochemical properties and the yield have a great influence, and the conditions for controlling the above influencing factors can be obtained, and a sustained-release microsphere preparation having a uniform particle diameter can be obtained, which is provided by the present invention.
  • Release microsphere size generally between 0.5 ⁇ 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 polylactic acid/glycolic acid blends and other pharmaceutically acceptable topical injection controlled release materials.
  • 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- ⁇ -hydroxybutyrate
  • 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 talazoparib pharmaceutical composition provided by the present invention can be implemented in the form of a talazoparib oil needle preparation. The release behavior described now.
  • the Talazoparib oil needle preparation comprises the active ingredient talazoparib, an excipient for release rate regulation and/or a pharmaceutically injectable solvent, and/or a small molecule regulator;
  • the talazoparib 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, even more preferably 1 to 20 parts by weight of the active ingredient talazoparib; 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 to 300 parts by weight Parts by weight, more preferably 0.1-100 parts by weight, still more preferably 0.1-10 parts by weight of a small molecule regulator;
  • the release rate modifying excipient is selected from the group consisting of medicinal oils, surfactants, or polymers.
  • the surfactant may be selected from the group consisting of phospholipids for injection, polysorbate 80, and polysorbitol.
  • the medicinal oil or fat may be selected from the group consisting of glycerin and 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 oil Acid triglyceride or caprylic acid triglyceride), glycerol oleic acid or a mixture thereof with a phospholipid and a combination of one or more of the corresponding salts;
  • the polymer is selected from the group consisting of sodium carboxymethyl cellulose and vinyl acetate One or a combination of two or more of an ester copolymer, a poloxamer, a polyethylene glycol, a hydroxylactic
  • 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 may be selected from the group consisting of sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, sodium carbonate, sodium hydrogencarbonate, meglumine, arginine, One or a combination of two or more of triethanolamine, citric acid, sodium chloride, glucose, 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 talazoparib in a pharmaceutically acceptable injectable solvent, adding a release rate adjusting auxiliary material and a small molecule regulator to uniformly mix, or directly reacting the activity.
  • the drug talazoparib, 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 talazoparib in the oil needle preparation provided by the present invention ranges from 0.1 to 200 mg, preferably from 0.5 to 100 mg; the talazoparib oil needle preparation provided by the present invention can be administered subcutaneously or intramuscularly, preferably by subcutaneous injection. .
  • Experimental animals Beagle dogs, male and female, weighing 8 to 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.
  • the gel preparation was placed in a vial containing 0.5% Tween 80 aqueous solution, sealed and sealed, and shaken at 37 ° C in a constant temperature water bath shaker at a rotation speed of 50 rpm with an amplitude of 24 mm. Samples were taken at the set time point, the sample volume was 3ml, and the corresponding amount of constant temperature distilled water was added. After the sample was released, it was diluted with 0.5% Tween 80 aqueous solution and determined by UV-visible spectrophotometry. The cumulative release was measured in parallel 3 times and averaged. And draw the release curve, the results are shown in Figure 1.
  • the Talazoparib and PLGA were dissolved in dichloromethane (50 ml), and injected into a BUCHI B- 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.
  • 290 spray-drying electrostatic collection system to prepare microspheres with uniform particle size 80% of the microspheres have a particle size of 0.5-10 ⁇ m.
  • the talazoparib microspheres were incubated in a release medium containing 0.2% Tween 80 in physiological isotonic PBS solution (pH 7.4). At 37 ° C, 100 r / min, at a predetermined time point, 5 ml of the dissolution medium was taken and centrifuged at 10,000 rpm for 5 min. After that, 20 ⁇ l of the supernatant was accurately weighed into a liquid chromatograph, and the chromatogram was recorded, and a cumulative drug release profile was made.
  • the sustained release microspheres released Talazoparib in less than 20% in one hour and about 20% in 120 hours.
  • the drug release was continued at 192 hours, and the cumulative release was less than 30%.
  • Preparation of Talazoparib polycystic liposomes comprises the following steps: (1) first dissolving a prescribed amount of cholesterol, dioleoylphosphatidylcholine (DOPC), dipalmitoylphosphatidylglycerol (DPPG), triolein 5 ml of chloroform-diethyl ether (1:1, v/v) solution as a lipid phase; then the prescribed amount of talazoparib, sucrose was dissolved in 5 ml of 60 mM hydrochloric acid solution as an internal aqueous phase; Adding the upper layer of the lipid phase, stirring with a high-speed shear homogenizer at 14000 rpm for 8 min to obtain W/O type colostrum; (2) adding the above colostrum to 10 ml containing 5 mg/ml glucose and 40 mmol/L lysine In the outer aqueous phase, mix with a high-speed shear homogenizer at 6000 rpm for 40 s to
  • Nitrogen and chloroform in the double emulsion were removed by nitrogen in a water bath at 37 ° C, and the polycapsule liposome suspension was added; (4) An appropriate amount of physiological saline was added to the Erlenmeyer flask, and then the liposome was separated by centrifugation at 6000 rpm for 10 min. The supernatant was discarded, and the precipitate was redispersed in an appropriate amount of physiological saline, and then precipitated by centrifugation. This was cycled three times, and the precipitate was concentrated, and the precipitate was diluted with an appropriate amount of physiological saline to obtain a talazoparib polycapsule liposome.
  • the prepared talazoparib polycapsule liposome suspension was placed in a physiological saline solution containing 0.5% Tween 80, and the resulting suspension was placed in a 37 ° C constant temperature shaker (rotation speed of 100 rpm) at a predetermined At the time point, 3 ml of the sample was taken out, and the same volume of physiological saline containing 0.5% Tween 80 was added; after the sample was properly diluted, the solution containing 0.5% Tween 80 physiological saline was used as a blank and determined by ultraviolet-visible spectrophotometry. The cumulative release was calculated and measured in parallel for 3 times and averaged. And draw the release curve, the results are shown in Figure 3.
  • the preparation of the Talazoparib 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, and standby; (2) grinding the Talazoparib tosylate and mixing with the wetting agent polysorbate 80, adding a suitable amount of water for injection to make a suspension; (3) slowly adding the dispersion medium 1 to the suspension under stirring (4) adding sodium dihydrogen phosphate dihydrate, anhydrous disodium hydrogen phosphate, sodium chloride, and adding water to volume; (5) stirring the constant volume of the suspension continuously for 60-120 minutes to fully mix (6) Finally, it is packaged in a sterilized and dried ampoules bottle or sealed in a glass bottle to obtain a talazoparib suspension.
  • the talazoparib 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 containing 0.5% Tween 80 was added, and then the tube containing the gel was placed in a constant temperature oscillator. The temperature was controlled at 37.0 ° C ⁇ 0.5 ° C and the rotational speed was 50 r / min. The entire dissolution process seals the tube to prevent evaporation of water and affect the results of the experiment.
  • the absorbance was measured at a wavelength of 255 nm, and the dissolution rate of the capsule was measured.
  • the release results are shown in Figure 5.
  • the active ingredient talazoparib in the immediate release capsule is released over 80% in about 30 minutes, and the basic release is complete within 1 hour.
  • in-situ gel formulation provides a plasma concentration C max reduction to 8800.0pg / mL, decreased by about 43%; when the drug is still visible result graph 6,
  • the in situ gel preparation can quickly reach the blood concentration required for PARP enzyme inhibition, and can be maintained in the effective blood concentration range for a longer period of time, avoiding excessive peak blood concentration and reducing drug side effects.
  • better enzyme inhibition and anti-tumor effects are provided, which also provides more room for drug dose climbing and optimal drug efficacy.

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Abstract

L'invention concerne une composition pharmaceutique contenant un Talazoparib inhibiteur de PARP et ses applications dans le traitement de tumeurs. La composition comprend spécifiquement les composants suivants en parties en poids : 0,1 à 200 parties de Talazoparib, 0,1 à 500 parties d'excipient pour réguler un taux de libération, 0 à 1000 parties de régulateur de petite molécule, et 0 à 2000 parties de solvant pharmaceutiquement injectable. La composition peut maintenir en continu la concentration plasmatique efficace et le niveau d'inhibition de l'activité enzymatique de PARP du Talazoparib dans un corps.
PCT/CN2017/116573 2016-12-16 2017-12-15 Composition pharmaceutique de talazoparib et ses applications WO2018108163A1 (fr)

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WO2023122292A1 (fr) * 2021-12-23 2023-06-29 Boston Scientific Medical Device Limited Compositions chimioemboliques et méthodes de traitement les utilisant
CN116531379A (zh) * 2023-03-14 2023-08-04 山东大学 一种布瑞哌唑缓释组合物及其制备方法与应用

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

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WO2015192014A1 (fr) * 2014-06-13 2015-12-17 Calithera Biosciences, Inc. Traitement combiné avec des inhibiteurs de glutaminase

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US11246836B2 (en) * 2018-05-17 2022-02-15 Bluelight Pharmatech Co., Ltd. Intramuscular depot of decoquinate compositions and method of prophylaxis and treatment thereof
WO2023122292A1 (fr) * 2021-12-23 2023-06-29 Boston Scientific Medical Device Limited Compositions chimioemboliques et méthodes de traitement les utilisant
CN116531379A (zh) * 2023-03-14 2023-08-04 山东大学 一种布瑞哌唑缓释组合物及其制备方法与应用

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