WO2018108163A1 - 一种Talazoparib药物组合物及其应用 - Google Patents

一种Talazoparib药物组合物及其应用 Download PDF

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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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talazoparib
parts
weight
acid
oil
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PCT/CN2017/116573
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English (en)
French (fr)
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甘勇
朱全垒
郭仕艳
朱春柳
张馨欣
宋文艺
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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/zh

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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—Liposomes
    • 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

一种包含PARP抑制剂Talazoparib的药物组合物及其用于治疗肿瘤的用途，所述组合物具体包含（重量份）： Talazoparib 0.1-200，释放速率调节用辅料 0.1-500，小分子调节剂 0-1000，药用可注射溶剂 0-2000。所述组合物可持续维持Talazoparib在体内的有效血药浓度和PARP酶活性抑制水平。

Description

一种Talazoparib药物组合物及其应用 技术领域
本发明涉及药物制剂领域和生物学领域，具体涉及一种应用于肿瘤的PARP酶抑制剂Talazoparib药物组合物及其用于治疗癌症的用途，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PARP酶抑制活性。
背景技术
Talazoparib是辉瑞公司于2016年8月收购生物制药公司Medivation,Inc.后，获得的一款新型PARP抑制剂，Talazoparib的分子式为C19H14F2N6O，分子量为380.35，具有下述化学结构：
Figure PCTCN2017116573-appb-000001
人体每个细胞每天会发生成千上万的DNA损伤，DNA损伤有两种，单链断裂和双链断裂。PARP(聚腺苷二磷酸-核糖聚合酶)主要修复单链断裂，BRCA1和BRCA2基因编码的蛋白通过同源重组(HR)通路参与DNA双链损伤的修复。而在肿瘤细胞中，Talazoparib等PARP抑制剂使得PARP活性受到抑制，致使细胞中单链DNA断裂损伤不被修复并积聚，持续的单链DNA损伤在DNA复制过程中将转化为双链DNA损伤，由于BRCA1/2基因功能缺陷的肿瘤细胞不能通过HR修复双链DNA损伤，这将导致DNA复制叉的停止，产生细胞毒性，导致合成致死，最终靶向杀死肿瘤细胞。
作为具有对DNA双链重组修复功能缺陷性肿瘤细胞的特异性靶向杀伤作用的“最强效”PARP酶抑制剂，Talazoparib在抗肿瘤等多个领域也吸引了众多科研工作者的眼球。然而，这种强效作用和非可逆的酶抑制机制，也使之在临床上的毒副作用明显，到目前为止，仍无具体的临床数据优势显现或报道。
据临床药动数据结果可见(J Clin Oncol，2013(31):abstr 2580)，Talazoparib单次口服后，吸收较快，1-2小时即可达最大吸收峰；I期临床研究发现，在25-1100μg/天的单剂量下，Talazoparib的系统暴露量随着剂量增加而成比例增加；25-1100μg/d的多剂量给药情况下，第二周末达稳态血药浓度，28天后的平均Cmax＝0.30-25.4ng/mL，平均AUC0-24h＝3.96-203ng*hr/mL。在900μg/d和1100μg/天剂量下，分别有1/6和2/5的患者出现了不可控的血小板减少症，最终确定II期临床剂量为1000μg/天。最终推荐的II期临床剂量为1mg/次/天，该剂量下，Talazoparib的血浆半衰期较长(>40h，也有数据报道>100小时)，稳态血药波峰和波谷浓度分别为50nM(19.02ng/mL)和10nM(3.80ng/mL)。
剂量限制毒性明显和血药浓度波动范围大导致在研的Talazoparib口服速释胶囊在临床运用的过程中，显示出较多的局限性：1)速释胶囊虽可快速达PARP酶抑制所需的血药浓度水平，但药物吸收较快，血药浓度波动范围大，稳态血药浓度峰值高于PARP酶抑制所需浓度几倍甚至十几倍，产生较严重的毒副作用；2)较高的稳态血药浓度波峰值产生的剂量限制毒性阻碍剂量的进一步提升，较大的血药浓度波动范围使药物不能长时间维持体内PARP酶抑制所需的血药浓度，阻碍了药效的进一步提升；3)药物口服剂量较小，对固体制剂的制备过程提出较高的要求。
为进一步改善Talazoparib的临床抗肿瘤疗效，并降低药物的毒副作用，有必要提供一种可稳定维持PARP酶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Talazoparib药物组合物，通过控制其释放行为，精确调控Talazoparib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PARP酶抑制水平的长期稳态，提高Talazoparib的抗肿瘤疗效，减少用药后的不良反应。
经专利检索，目前尚无公开的与Talazoparib有关的制剂专利。为进一步提高Talazoparib的临床疗效，本发明公开了一种可精确调控Talazoparib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酶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PARP酶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。
发明内容
Talazopari多剂量给药后，往往产生较高的稳态血药波峰/波谷比值，即较大的血药浓度波动，加之该药物对PARP酶的不可逆性抑制作用，导致Talazoparib的速释胶囊制剂存在众多安全性问题，限制了其临床疗效的进一步提升和发挥。
本发明的首要目的是针对Talazoparib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PARP酶抑制水平可控的Talazoparib药物组合物，以进一步提高Talazoparib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Talazoparib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他们作为唯一制剂或其他疗法联合治疗癌症的用途。
Talazoparib属于难溶性药物，本发明所提供的Talazoparib药物组合物中的活性成分Talazoparib可以是Talazoparib的游离碱形式，也可以是其药学上可接受的盐形式的化合物，例如Talazoparib甲苯磺酸盐，Talazoparib盐酸盐，Talazoparib硫酸盐，Talazoparib马来酸盐和Talazoparib樟脑酸盐等。因此，在本发明药物组合物中的活性成分Talazoparib包括Talazoparib的游离碱和其药学上可接受的盐。
本发明提供了一种Talazoparib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Talazoparib；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0.1-100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，优选0.5-2000重量份的药用可注射溶剂。
本发明所述的组合物中的药物释放速率调节用辅料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聚合物、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，药用可生物降解聚合物可为选自：聚乳酸(PLA)、聚乳酸-羟基乙酸共聚物(PLGA)、聚原酸酯类、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、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可为选自：注射用磷脂、Solutol HS15、聚山梨醇酯、聚氧乙烯蓖麻油、泊洛沙姆、聚氧乙烯脂肪酸酯、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。所述药用油脂可为选自：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)和其他的药用油脂(例如油酸甘油酯，如单油酸甘油酯，双油酸甘油酯，三油酸甘油酯以及它们与磷脂等的混合物等)以及相应盐中的一种或两种以上的组合。
所述小分子调节剂具体地可为选自渗透压或酸碱度(pH)调节剂，如：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。
所述药用可注射溶剂可为选自：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、甘油糖醛、甘油缩甲醛、丙二醇、乙醇、乙二醇二乙醚和其他可药用的注射溶剂中的一种或两种以上的组合。
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、肌肉以及其他部位的注射或埋植。
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缓控释局部注射递药系统(如SABER delivery system和Camurus FluidCrystal injection系统等)等。
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1mL。
鉴于Talazoparib对PARP酶抑制活性的非可逆性抑制机制，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。
本发明提供的Talazoparib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，6小时内释放量小于Talazoparib总量的20％，优选小于10％，甚至可小于5％；24h释放量小于Talazoparib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14天或大于30天。
与目前在研的临床制剂——速释胶囊相比，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PARP酶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0.2-50ng/mL的范围内，甚至血药浓度大于2ng/mL<C<25ng/mL维持7天以上。血药浓度波动的降低以及长期高效的PARP酶抑制效果，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。
本发明提供了所述Talazoparib药物组合物在制备用于治疗和/或预防具有肿瘤(如卵巢癌、乳腺癌、胃癌等)的药物中的用途。
本发明提供的Talazoparib药物组合物可用于肿瘤(如卵巢癌、乳腺癌、胃癌等)的临床治疗。
与口服普通速释制剂相比，具有如下优点：
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高效肿瘤抑制水平，药效持久；
2)可控的药物吸收速率，控制血药浓度水平和波动范围，减小患者用药后的不良反应；
3)单次注射或埋植后，可维持较长时间的有效PARP酶抑制，减少了普通制剂每天用药的繁琐过程，更加方便临床用药；
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。
为更好地阐述本发明提供的talazoparib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。
附图说明
图1显示实施例1talazoparib原位沉淀型凝胶制剂的体外释放曲线。
图2显示实施例2talazoparib缓释微球的体外释放曲线。
图3显示实施例3talazoparib多囊脂质体的体外释放曲线。
图4显示实施例6talazoparib原位温敏凝胶制剂的体外释放曲线。
图5显示对比实施例1的速释talazoparib胶囊的释放曲线。
图6显示对比实施例1的速释talazoparib胶囊和实施例1中的talazoparib原位凝胶注射液的犬体内药时曲线图。
具体实施方式
1.多囊脂质体
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。
本发明的talazoparib药物组合物可以为talazoparib多囊脂质体形式，其中所述talazoparib多囊脂质体组合物包含活性成分talazoparib、脂质成分(包括油脂和表面活性剂)以及非必须的其他可药用的pH/渗透压调节剂中的一种或两种以上的组合；其中，所述talazoparib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talazoparib；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重量份的其他可药用的脂质膜流动性调节剂/pH/渗透压调节剂。
所述talazoparib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talazoparib，未被多囊脂质体装载的游离talazoparib的量一般小于组合物中talazoparib总量的20％，优选小于10％。
所述脂质成分选自至少一种两亲性脂质和/或至少一种中性脂质；所述两亲性脂质包括磷脂酰胆碱或磷脂酰甘油或相应盐或以上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，磷脂酰胆碱可以选自DEPC或DOPC或它们的组合物；所述中性脂质包括乙二醇酯，角鲨烯、甘油、甘油三酯和丙二醇酯或以上成分的混合物等，在具体的实例中甘油三脂可以选自油酸甘油三酯或辛酸甘油三酯。
在某些实例中，组合物优选包括脂质膜流动性调节剂、渗透压调节剂和/或pH调节剂；所述脂质膜流动性调节剂可以选自胆固醇或植物甾醇等；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。
多囊脂质体组合物制剂中的活性成分talazoparib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talazoparib量占组合物中talazoparib总量的0-20％。
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。
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乙醚的混合液)形成油相，将处方量的talazoparib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(乙醚、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。
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。
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Talazoparib多囊脂质体。
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Talazoparib总量的20％，优选小于10％，甚至小于5％；24h释放量小于Talazoparib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PARP酶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0.2-50ng/mL的范围内，甚至血药浓度大于2ng/mL<C<25ng/mL维持7天以上。
2.混悬剂
本发明提供的talazoparib药物组合物可以通过talazoparib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。
Talazoparib混悬剂包含活性成分talazoparib，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；
其中，所述talazoparib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talazoparib；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。
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， 所述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，聚合物可包括羧甲基纤维素钠、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。
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、乙二醇二乙醚中的一种或两种以上的组合。
所述缓冲剂可选自磷酸钠、磷酸氢二钠、磷酸二氢钠、磷酸钾、柠檬酸钠、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。
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。
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。
本发明提供的混悬剂中的活性成分talazoparib的单次给药量范围是0.1-200mg，优选0.5-100mg；本发明提供的talazoparib混悬剂可皮下或肌肉注射给药，优选皮下注射给药。
3.原位凝胶
原位凝胶植入剂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。
本发明提供的talazoparib药物组合物可以通过talazoparib原位凝胶系统的形式实现所述的释放行为，其特征在于，该原位凝胶系统包含活性成分药物talazoparib、适宜的溶剂、释放速率调节用凝胶形成材料。其中，所述talazoparib原位凝胶系统包含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talazoparib；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。
所述talazoparib原位凝胶系统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talazoparib，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系统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。还可将聚丙交酯/乙交酯-聚乙二醇共聚物和/或其共混物、泊洛沙姆或聚己内酯-聚乙二醇共聚物等材料和其它药用添加剂溶解于水中，制备温敏型凝胶制剂，与活性药物的溶液混合或与活性药物分别预装在无菌注射器临用前混合后局部注射至人体后形成凝胶材料，调节药物释放速率。
本发明所述的原位凝胶系统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、乙二醇二乙醚、苯甲醇、二甲亚砜及其他药学可应用的有机溶剂中的一种或两种以上的组合。
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、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、泊洛沙姆以及其他药学可应用局部注射用缓控释材料中的一种或两种以上的组合。
原位凝胶系统中的活性成分talazoparib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。
本法明所提供的Talazoparib原位凝胶系统，于6小时内释放量小于制剂中Talazoparib总量的20％，甚至小于15％；24h释放量小于Talazoparib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Talazoparib原位凝胶系统注射给药后，可快速达到有效抗肿瘤PARP酶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0.2-50ng/mL的范围内，甚至血药浓度大于2ng/mL<C<25ng/mL维持7天以上。
本发明提供的原位凝胶系统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。
本发明提供的原位凝胶系统可静脉、皮下或肌肉注射给药，优选皮下和肌肉注射给药。
4.微球
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系统决定。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。
本发明所述释放行为的药物组合物可以talazoparib微球的方式提供，所述talazoparib微球包含活性成分talazoparib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talazoparib，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。
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，优选选自甘油、聚乙二醇、0.1wt％-1wt％Tween80的水溶液中的一种或两种以上组合。
所述talazoparib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talazoparib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系统喷雾干燥收集制备；Talazoparib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0.2ml/min-1ml/min的速率缓慢注射入喷雾干燥静电系统(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，收集静电收集系统壁上的微球粉末即可，药物和聚合物溶液的浓度，系统的进样速率，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/羟乙酸共混物以及其他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。
本发明提供的微球系统可以固体粉末形式长期贮存。
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。
5.油针制剂
本发明提供的talazoparib药物组合物可以通过talazoparib油针制剂的形式实施，以实 现所述的释放行为。
Talazoparib油针制剂包含活性成分talazoparib，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；
其中，所述talazoparib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重量份的，甚至更优选1-20重量份的活性成分talazoparib；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；
在某些实施例中，所述释放速率调节用辅料选自药用油脂、表面活性剂或聚合物，例如，所述表面活性剂可选自注射用磷脂、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；所述药用油脂可选自：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；
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、乙二醇二乙醚中的一种或两种以上的组合；
所述小分子调节剂可选自磷酸钠、磷酸氢二钠、磷酸二氢钠、磷酸钾、磷酸氢二钾、磷酸二氢钾、碳酸钠、碳酸氢钠、葡甲胺、精氨酸、三乙醇胺、枸橼酸、氯化钠、葡糖糖和甘露醇中的一种或两种以上的组合。
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talazoparib溶解于药用可注射溶剂中，再加入释放速率调节用辅料和小分子调节剂混合均匀，或直接将活性药物talazoparib、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。
本发明提供的油针制剂中的活性成分talazoparib的单次给药量范围是0.1-200mg，优选0.5-100mg；本发明提供的talazoparib油针制剂可皮下或肌肉注射给药，优选皮下注射给药。
实施例
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。
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。
实施例1 talazoparib原位沉淀型凝胶制剂的制备
Figure PCTCN2017116573-appb-000002
称取处方量的PLA(分子量为10000)至N-甲基吡咯烷酮中，搅拌溶解，再加入药物talazoparib缓慢搅拌，直至药物溶解并呈现均一的状态，即得talazoparib原位沉淀型凝胶注射液。
取凝胶制剂置于装有0.5％吐温80水溶液的小瓶中，加盖密封，于恒温水浴锅振荡仪37℃中，转速为50rpm，振幅为24mm。分别在设定的时间点取样，取样量为3ml，同时补充相应量的恒温的蒸馏水，释放样品经合理稀释后，以0.5％吐温80水溶液为空白，采用紫外-可见分光光度法测定，计算累积释放度，平行测定3次，取平均值。并绘制释放曲线，结果见图1。
图1结果显示：原位沉淀型凝胶制剂在12小时内释放Talazoparib量小于20％，144小时内释放80％左右。
实施例2 talazoparib微球的制备
Figure PCTCN2017116573-appb-000003
以二氯甲烷(50ml)溶解Talazoparib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喷雾干燥静电收集系统，制备粒径均匀的微球，80％的微球粒径为0.5-10μm。
取talazoparib微球置于含0.2％Tween 80的生理等渗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，取溶出介质5ml，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，并作出药物累积释放曲线图。
结果见图2，缓释微球于1小时内释放Talazoparib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％。
实施例3 talazoparib多囊脂质体的制备
Figure PCTCN2017116573-appb-000004
Talazoparib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5ml量的氯仿-乙醚(1:1，v/v)溶液中，作为脂质相；再将处方量的talazoparib、蔗糖用5ml 60mM的盐酸溶液溶解，作为内水相；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；(2)将上述初乳加入到10ml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；(3)将复乳转移至盛有外水相的锥形瓶中，通以氮气于37℃水浴除去复乳中的乙醚和氯仿，得多囊脂质体混悬液；(4)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talazoparib多囊脂质体。
取制备的talazoparib多囊脂质体混悬液，置于含有0.5％吐温80的生理盐水溶液中，将得到的混悬液置于37℃恒温摇床(转速为100rpm)中，在预定的时间点取出3ml样品，并补加相同体积含有0.5％吐温80的生理盐水；将取出的样品经合理稀释后，以含有0.5％吐温80生理盐水为空白，采用紫外-可见分光光度法测定，计算累积释放度，平行测定3次，取平均值。并绘制释放曲线，结果见图3。
图3结果显示：制备的多囊脂质体在24小时释放约为10％，120小时释放约为30％，168小时释放约为50％。
实施例4 talazoparib混悬剂的制备
Figure PCTCN2017116573-appb-000005
Figure PCTCN2017116573-appb-000006
Talazoparib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Talazoparib甲苯磺酸盐研磨后与润湿剂聚山梨醇酯80混匀，加入适量的注射用水制成混悬液；(3)在搅拌状态下将分散介质1缓慢加入混悬液中；(4)加入磷酸二氢钠二水合物、无水磷酸氢二钠、氯化钠，加水定容；(5)将定容好的混悬液不断搅拌60-120min，使其充分混匀；(6)最后将其分装于灭菌干燥的安瓿瓶中熔封或玻璃瓶中封口，即得talazoparib混悬剂。
实施例5 talazoparib油针制剂的制备
Figure PCTCN2017116573-appb-000007
称取处方量的苯甲醇和苯甲酸苄酯涡旋2min，混合均匀后加入处方量的Talazoparib原料药，涡旋5min，超声2min，使其呈现均一的状态；再加入处方量的大豆油，涡旋2min，并在室温条件下搅拌2小时使其混合均匀；将其分装于灭菌干燥的安剖瓶中，通入无菌氮气，并熔封，得到talazoparib油针制剂。
实施例6 talazoparib原位温敏凝胶制剂的制备
Figure PCTCN2017116573-appb-000008
称取处方量的PLGA-PEG-PLGA共聚物(丙交酯与乙交酯的摩尔比＝3:1，聚乙二醇质量百分比25％，聚乙二醇数均分子量为1000)，加入适量的注射用水中，搅拌直至聚合物分散均匀，于4℃条件保存至凝胶充分溶胀，将处方量的talazoparib盐酸盐加入上述凝胶溶液中搅拌均匀，继续加入注射用水至处方量，即得talazoparib温敏凝胶。
取talazoparib原位温敏凝胶置于试管中，于恒温振荡仪37℃下形成凝胶，10min后加入含有0.5％吐温80的生理盐水，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50r/min。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恒温的含有0.5％吐温 80的生理盐水介质，样品经合理稀释后，采用紫外-可见分光光度法测定，然后计算累计释放度，并绘制释放曲线。每个样品测定3次，取平均值，结果见图4。
图4结果显示：温敏凝胶制剂于8小时内释放Talazoparib量小于20％，120小时内释放80％左右，持续释放时间为7天。
对比实施例1速释胶囊
自制速释胶囊，将25wt％talazoparib甲苯磺酸盐、33wt％微晶纤维素、22wt％乳糖、15wt％甘露醇、2wt％微粉硅胶、1wt％硬脂酸镁和2wt％十二烷基硫酸钠混合均匀后，直接装入0#硬胶囊制成；其溶出度测定是采用溶出度测定法(中国药典2010年版二部附录X C)第一法装置，37℃条件下，以900mL pH 1.2的盐酸水溶液为释放介质，转速为每分钟75转，依法操作，按预定时间点取溶液6mL，离心，取上清液作为供试品溶液，测定释放度。
按照紫外-可见分光光度法(中国药典2010年版二部附录ⅣA)，在255nm的波长处分别测定吸光度，测定胶囊的溶出度。
释放结果见图5。速释胶囊中活性成分talazoparib于30分钟左右释放80％以上，1小时内基本释放完全。
实验实施例1
1mg当量的对比实施例1的talazoparib速释胶囊给药与空腹比格犬(n＝3)，用25mL水送服，1mg当量的实施例1的talazoparib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，离心10min，取上层血浆，用于LC-MS的血药浓度检测，结果见示例图6。相对于胶囊制剂的Cmax(15344.5pg/mL)，原位凝胶制剂提供的血药浓度的Cmax降低至8800.0pg/mL，降低了约43％；由药时曲线图6结果仍可见，相对于速释胶囊，原位凝胶制剂可快速达PARP酶抑制所需血药浓度，可更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。

Claims (12)

  1. Talazoparib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Talazoparib；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0.1-100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。
  2. 根据权利要求1所述的Talazoparib药物组合物，其中，
    所述活性成分Talazoparib包括Talazoparib的游离碱和其药学上可接受的盐形式化合物，优选地，所述盐形式化合物选自Talazoparib甲苯磺酸盐，Talazoparib盐酸盐，Talazoparib硫酸盐，Talazoparib马来酸盐和Talazoparib樟脑酸盐；
    所述释放速率调节用辅料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聚合物、药用油脂、药用表面活性剂中的一种或两种以上的组合；
    优选地，所述药用可生物降解的聚合物为选自：聚乳酸(PLA)、聚乳酸-羟基乙酸共聚物(PLGA)、聚原酸酯类、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、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，
    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，
    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；和/或
    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
    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、乙二醇二乙醚中的一种或两种以上的组合。
  3. 根据权利要求1或2所述的Talazoparib药物组合物，其中，所述Talazoparib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Talazoparib总量的20％，优选小于10％，甚至可小于5％；24h释放量小于Talazoparib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14天或大于30天。
  4. 根据权利要求1至3中任一项所述的Talazoparib药物组合物，其中，所述Talazoparib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PARP酶所需的血药浓度几天，甚至数十天，例如该有效血药浓度可几天至几十天维持在0.2-50ng/mL的范围内，甚至血药浓度大于2ng/mL<C<25ng/mL维持7天以上，进而维持在有效的PARP酶抑制水平数天，甚至数十天，增加药物抗肿瘤疗效。
  5. 根据权利要求1至4中任一项所述的Talazoparib药物组合物，其中，所述Talazoparib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系统。
  6. 根据权利要求1至4中任一项所述的Talazoparib药物组合物，其中，
    所述Talazoparib药物组合物为talazoparib多囊脂质体，
    优选地，所述talazoparib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talazoparib；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；
    优选地，所述talazoparib多囊脂质体包括未被多囊脂质体包裹的游离talazoparib，未被多囊脂质体装载的游离talazoparib的量一般小于组合物中talazoparib总量的20％，优选小于10％；
    优选地，所述脂质成分选自至少一种两亲性脂质和/或至少一种中性脂质；
    优选地，所述两亲性脂质包括磷脂酰胆碱或磷脂酰甘油或相应盐或以上两种以上成分的组合；
    优选地，磷脂酰甘油是二棕榈酰磷脂酰甘油(DPPG)，磷脂酰胆碱选自二芥酰基卵磷脂(DEPC)或二油酰磷脂酰胆碱(DOPC)或它们的组合物；
    优选地，所述中性脂质包括乙二醇酯、角鲨烯、甘油、甘油三脂和丙二醇酯或以上两种以上成分的混合物；
    优选地，甘油三脂选自油酸甘油三酯或辛酸甘油三酯；
    优选地，所述脂质膜流动性调节剂选自胆固醇或植物甾醇；
    所述pH调节剂选自非有机酸，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；
    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；
    优选地，所述talazoparib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；
    优选地，所述talazoparib多囊脂质体于6小时内释放量小于制剂中Talazoparib总量的20％，优选小于10％，甚至小于5％；24h释放量小于Talazoparib总量的40％，优选小于30％，甚至小于20％；90％药物释放时间>3天。
  7. 根据权利要求1至4中任一项所述的Talazoparib药物组合物，其中，
    所述Talazoparib药物组合物为Talazoparib混悬剂，
    优选地，所述Talazoparib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talazoparib；0-2000重量份，优选0-1000重量份，更优选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；
    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；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；
    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、乙二醇二乙醚中的一种或两种以上的组合；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、碳酸钠、柠檬酸钠、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；
    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；
    优选地，所述Talazoparib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。
  8. 根据权利要求1至4中任一项所述的Talazoparib药物组合物，其中，
    所述Talazoparib药物组合物为talazoparib原位凝胶系统，
    优选地，所述talazoparib原位凝胶系统包含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talazoparib；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，甚至更优选1-100重量份的释放速率调节用凝胶形成材料；
    优选地，所述溶剂为选自水、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、乙二醇二乙醚、苯甲醇、二甲亚砜中的一种或两种以上的组合；
    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；
    优选地，所述原位凝胶系统中的talazoparib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；
    优选地，所述Talazoparib原位凝胶系统，于6小时内释放量小于制剂中Talazoparib 总量的20％，甚至小于15％；24h释放量小于Talazoparib总量的40％，甚至小于30％；90％药物释放时间>3天；
    优选地，所述原位凝胶系统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；
    优选地，所述原位凝胶系统通过静脉、皮下或肌肉注射给药，优选皮下和肌肉注射给药。
  9. 根据权利要求1至4中任一项所述的Talazoparib药物组合物，其中，
    所述Talazoparib药物组合物为缓释微球，
    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talazoparib；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；
    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％Tween80水溶液中的一种或两种以上组合；
    优选地，所述缓释微球粒径分布在0.5～20μm之间；
    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；
    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。
  10. 根据权利要求1至4中任一项所述的Talazoparib药物组合物，其中，
    所述Talazoparib药物组合物为Talazoparib油针制剂，
    优选地，所述Talazoparib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talazoparib；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；
    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；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；
    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、乙二醇二乙醚中的一种或两种以上的组合；；
    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、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、枸橼酸、氯化钠、葡糖糖和甘露醇中的一种或两种以上的组合。
  11. 根据权利要求1至10中任一项所述的Talazoparib药物组合物在制备用于治疗和/或预防肿瘤的药物中的用途。
  12. 根据权利要求11所述的用途，其中Talazoparib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。
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