CN108210461A - A kind of Talazoparib pharmaceutical compositions and its application - Google Patents

Abstract

The invention discloses a Talazoparib pharmaceutical composition and application thereof. The composition comprises 0.1-200 parts by weight of Talazoparib, 0.1-500 parts by weight of excipients for regulating the release rate, 0-10 parts by weight of small molecule regulators, and 0-2000 parts by weight of a pharmaceutically acceptable injectable solvent. The composition has controllable drug release behavior and can maintain the effective blood drug concentration and PARP enzyme activity inhibition level of the compound in vivo. The present invention realizes the control of Talazoparib blood drug concentration and drug effect level in the body by means of long-acting injection composition, improves drug therapeutic effect, prolongs action time, reduces drug toxic and side effects at the same time, and provides a high-efficiency, long-lasting, and less toxic and side effects PARP enzyme activity inhibiting pharmaceutical compositions. Also disclosed is the use of the talazoparib pharmaceutical composition for treating tumors with DNA repair function defects.

Description

A kind of Talazoparib pharmaceutical composition and application thereof

technical field

The present invention relates to the field of pharmaceutical preparations and the field of biology, in particular to a pharmaceutical composition of PARP enzyme inhibitor Talazoparib applied to DNA repair deficient tumors and its use for treating cancer, the pharmaceutical composition has controlled release Behavior, able to maintain a stable blood concentration in vivo and long-lasting PARP enzyme inhibitory activity.

Background technique

Talazoparib is a new PARP inhibitor obtained by Pfizer after acquiring the biopharmaceutical company Medivation, Inc. in August 2016. The molecular formula of Talazoparib is C ₁₉ H ₁₄ F ₂ N ₆ O, the molecular weight is 380.35, and it has the following chemical structure:

Thousands of DNA damages occur in each cell of the human body every day. There are two types of DNA damage, single-strand breaks and double-strand breaks. PARP (polyadenosine diphosphate-ribose polymerase) mainly repairs single-strand breaks, and the proteins encoded by BRCA1 and BRCA2 genes participate in the repair of DNA double-strand damage through the homologous recombination (HR) pathway. In tumor cells, PARP inhibitors such as talazoparib inhibit the activity of PARP, resulting in single-strand DNA breaks in cells not being repaired and accumulated, and continuous single-strand DNA damage will be converted into double-strand DNA damage during DNA replication. Tumor cells with defective BRCA1/2 gene function cannot repair double-strand DNA damage through HR, which will lead to the arrest of DNA replication forks, resulting in cytotoxicity, resulting in synthetic lethality, and ultimately targeted killing of tumor cells.

As the "most potent" PARP enzyme inhibitor with a specific targeted killing effect on DNA double-strand recombination repair function-deficient tumor cells, Talazoparib has also attracted the attention of many researchers in many fields such as anti-tumor. However, this strong effect and irreversible enzyme inhibition mechanism also make it clinically toxic and side effects are obvious, so far, there is still no specific clinical data advantage or report.

According to the results of clinical pharmacokinetic data, talazoparib is absorbed quickly after a single oral administration, and the maximum absorption peak can be reached in 1-2 hours; phase I clinical research found that under a single dose of 25-1100ug/day, the systemic exposure of talazoparib The amount increases proportionally with the dose increase; in the case of multiple dose administration of 25-1100μg/d, the steady-state plasma concentration is reached at the end of the second week, and the average Cmax=0.30-25.4ng/mL after 28 days, the average AUC _{0- 24h} = 3.96-203ng*hr/mL. Under the dosage of 900ug/d and 1100ug/day, 1/6 and 2/5 of the patients developed uncontrollable thrombocytopenia respectively, and finally determined the phase II clinical dosage as 1000ug/day. The final recommended phase II clinical dose is 1mg/time/day. At this dose, the plasma half-life of talazoparib is longer (>40h, and there are also data reports>100 hours), and the steady-state plasma peak and trough concentrations are 50nM (19.02ng /mL) and 10nM (3.80ng/mL), the peak value is about 5 times of the trough value.

The greater toxicity of the compound and the higher fluctuation range of blood drug concentration lead to the clinical application of Talazoparib oral immediate-release capsules under research, showing more limitations: 1) Although the immediate-release capsules can quickly reach the PARP enzyme The level of blood drug concentration required for inhibition, but the drug is absorbed quickly and the blood drug concentration is suddenly high, resulting in a large fluctuation range of the steady-state blood drug concentration of Talazoparib, and the peak value of the steady-state blood drug concentration is several times higher than the concentration required for PARP enzyme inhibition Even more than a dozen times, more serious toxic and side effects are produced; 2) The higher peak value of the steady-state blood drug concentration leads to more toxicity, which limits the further increase of the dose and the blood drug required for the inhibition of the drug PARP enzyme in the body The increase of the concentration hinders the further improvement of the drug effect; 3) the oral dose of the drug is relatively small, which puts forward higher requirements on the preparation process of the solid preparation.

In order to further improve the clinical antitumor efficacy of Talazoparib and reduce the toxic and side effects of the drug, it is necessary to provide an excellent composition form that can stably maintain the blood drug concentration required for PARP enzyme inhibition and reduce the peak/trough ratio of the blood drug concentration. The present invention The purpose is to develop a Talazoparib pharmaceutical composition, by controlling its release behavior, precisely regulate the absorption rate and absorption time of Talazoparib in the body, and then control the blood drug concentration level and its fluctuation range in the body, and maintain the blood drug concentration in the body at the level of the effective PARP enzyme. The long-term steady state of the inhibition level improves the antitumor efficacy of Talazoparib and reduces the adverse reactions after administration.

According to the patent search, there is currently no published patent on preparations related to Talazoparib. In order to further improve the clinical curative effect of talazoparib, the present invention discloses a controlled-release composition that can precisely regulate the blood drug concentration level and fluctuation range of talazoparib, and the composition can controllably regulate the long-term maintenance of the blood drug concentration level required for enzyme inhibition, At the same time, it reduces the fluctuation range of blood drug concentration, thereby improving the PARP enzyme inhibition rate of tumor cells and anti-tumor curative effect, reducing the adverse reactions of tumor patients after taking medicine, and increasing the compliance of patients taking medicine.

Contents of the invention

Talazoparib with a longer half-life, after multiple doses of administration, often produces a higher steady-state plasma peak/trough ratio (>5), that is, a large fluctuation in plasma concentration, coupled with the irreversible inhibitory effect of the drug on the PARP enzyme , resulting in many safety problems in the immediate-release capsule formulation of talazoparib, which limits the further improvement and exertion of its clinical efficacy.

The primary purpose of the present invention is to provide a Talazoparib pharmaceutical composition with controllable absorption behavior, blood drug concentration and PARP enzyme inhibition level in vivo for the biological properties of Talazoparib and the drug efficacy and safety requirements of clinical treatment, so as to further improve the Talazoparib It can reduce the adverse reactions of tumor patients after taking medicine, and increase the compliance of patients taking medicine. The present invention relates to novel combinations of drugs with improved Talazoparib drug loading and/or in vivo absorption and/or bioavailability and/or control of blood drug concentration and/or control of enzyme inhibition levels and their use as sole agents or in combination with other therapies for the treatment of cancer the use of.

Talazoparib belongs to insoluble medicine, and the active ingredient Talazoparib in the Talazoparib pharmaceutical composition provided by the present invention can be the free base form of Talazoparib, also can be the compound of its pharmacologically acceptable salt form, for example Talazoparib tosylate, Talazoparib hydrochloride, Talazoparib sulfate, Talazoparib maleate and Talazoparib camphorate etc. Therefore, the active ingredient Talazoparib in the pharmaceutical composition of the present invention includes the free base of Talazoparib and the pharmacologically acceptable salts thereof.

The invention provides a pharmaceutical composition of Talazoparib, which comprises 0.1-200 parts by weight of the active ingredient Talazoparib, 0.1-500 parts by weight of excipients for regulating the release rate, 0-10 parts by weight of small molecule regulators, 0 - 2000 parts by weight of a pharmaceutically acceptable injectable solvent.

The drug release rate regulating auxiliary material in the composition of the present invention is selected from pharmaceutical biodegradable polymers, medicinal oils, pharmaceutical surfactants and other pharmaceutical auxiliary materials (such as sucrose) that can realize local injection sustained release effect. Acetate isobutyrate) one or a combination of two or more; specifically, the pharmaceutical biodegradable polymer can be selected from: polylactic acid (PLA), polylactic acid-glycolic acid copolymer (PLGA), polyatomic acid Esters, sucrose acetate-isobutyrate, fatty acid glycerides, PEGylated PLA/PLGA, triethylene glycol poly(orthoester) polymer, chitosan, water-soluble carboxymethyl chitosan , fibroin, poly-β-hydroxybutyrate valerate, polylactide/lactide-polyethylene glycol copolymer or its blend, poly-β-hydroxybutyrate and polyethylene glycol blend One or more combinations of polylactic acid/glycolic acid blends and polylactic acid/glycolic acid blends. The pharmaceutical surfactant can be selected from: phospholipids for injection, Tween 20, Tween 80, Cremphor EL, Solutol HS 15, polysorbate 80, polysorbate 20, polyoxyethylene castor oil 60, Poloxamer 188, polyoxyethylene fatty acid ester, phosphatidylcholine (such as DEPC or DOPC or their composition), phosphatidylglycerol (such as DPPG) and other pharmaceutically acceptable surfactants or A combination of two or more. Described medicinal oil can be selected from: glycerin, cholesterol, propylene glycol ester, ethylene glycol ester, squalene, stearic acid, olive oil, soybean oil, coconut oil, castor oil, sesame oil, peanut oil, cottonseed oil, Triglycerides (such as triglyceride oleate or triglyceride caprylate) and other medicinal oils (such as glyceryl oleate, such as glyceryl monooleate, glyceryl dioleate, glyceryl trioleate and their combination with mixtures of phospholipids, etc.) and one or a combination of two or more of the corresponding salts.

The small molecule regulator can specifically be selected from osmotic pressure or pH (pH) regulators, such as: acetic acid, anhydrous citric acid, ascorbic acid, calcium chloride, phenol, edetate calcium disodium, edetate calcium disodium, edetate Sodium diolate, glycine, histidine, hydrochloric acid, lactic acid, lactose monohydrate, magnesium chloride, mannitol, methanesulfonic acid, methionine, phenol, phosphoric acid, anhydrous dipotassium hydrogen, sodium acetate, sodium ascorbate, sodium bicarbonate, Sodium bisulfate, 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 bicarbonate, glucose Methylamine, Protamine, Propylparaben, Cholesterol, Phytosterols, Arginine, Triethanolamine, Glucose, Sorbitol, Sucrose, Tartaric Acid, Tromethamine, Zinc Acetate, Zinc Chloride, Glucose One or a combination of two or more.

The pharmaceutical injectable solvent can be selected from: water, benzyl alcohol, chlorobutanol, dimethyl sulfoxide, methylpyrrolidone, propylene glycol, polyethylene glycol (mono) methyl ether, glyceryl triacetate benzyl benzoate , glycerol furfural, glycerol formal, propylene glycol, ethanol, ethylene glycol diethyl ether and other pharmaceutically acceptable injection solvents or a combination of two or more.

The storage form of the pharmaceutical composition provided by the present invention can be in the form of solution, suspension, freeze-dried powder or pre-filled syringe of drug powder or solution, which can be used for subcutaneous, intradermal, intramuscular and other injection or implantation.

The pharmaceutical composition provided by the present invention can be selected from suspensions available for local injection or implantation, oil injection preparations, sustained-release microspheres, implant gels, multivesicular liposomes and other applicable sustained-control agents. Release local injection drug delivery system (such as SABERdelivery system and Camurus FluidCrystal injection system, etc.), etc.

In the pharmaceutical composition provided by the present invention, the content of the active ingredient in the unit preparation before injection (drug content in a single injection preparation) is about 0.1 mg to 200 mg, preferably the drug content of the preparation is 0.5-100 mg, more preferably 1- 50 mg, even more preferably 1-20 mg, the volume required for a single local injection or implant in humans is 0.5-2 mL, preferably 1 mL per injection or implant.

In view of the irreversible inhibitory mechanism of talazoparib on PARP enzyme inhibitory activity, long-term high-concentration inhibition may lead to unacceptable toxic and side effects of the body. Therefore, it is not ruled out to give the body a certain "drug holiday" In the form of medicine, that is, after a period of time after taking medicine, after the medicine is absorbed and eliminated, the body can be given a certain recovery period before taking medicine again.

The Talazoparib pharmaceutical composition provided by the present invention has controllable drug release behavior, after injection or implant administration, within a predetermined period of time, its release behavior and release amount are controllable in a release medium that meets sink conditions, In aqueous medium, at 37°C, the release amount is less than 10%, or even less than 5% of the total amount of Talazoparib within 6 hours; the release amount is less than 30%, or even less than 20% of the total amount of Talazoparib within 24 hours; 90% drug release Time>3 days, even more than 7 days, more than 14 days or more than 30 days.

Compared with the clinical preparation currently under research - immediate-release capsules, the pharmaceutical composition provided by the present invention can quickly reach the blood drug concentration level required for effective anti-tumor PARP enzyme inhibition after injection, and can avoid blood drug Concentration fluctuates and remains at the effective blood concentration for several days, even tens of days. The effective blood drug concentration can be maintained within the range of 0.2ng/mL-50ng/mL for several to dozens of days, and even the blood drug concentration is greater than 2ng/mL<C<25ng/mL for more than 7 days. The reduction of blood concentration fluctuations and the long-term and efficient PARP enzyme inhibitory effect are expected to improve the anti-tumor efficacy, reduce the toxicity, and realize more efficient and low-toxic adjustable treatment and the regulation of dosing frequency for cancer patients.

The present invention provides the use of the Talazoparib pharmaceutical composition in the preparation of medicines for treating and/or preventing tumors with DNA repair function defects (such as ovarian cancer, breast cancer, gastric cancer, etc.).

The talazoparib pharmaceutical composition provided by the invention can be used for the clinical treatment of tumors with DNA repair function defects (such as ovarian cancer, breast cancer, gastric cancer, etc.).

Compared with oral ordinary immediate-release preparations, it has the following advantages:

1) It can realize the controllable release and absorption of drugs, provide accurate in vivo blood drug concentration and long-term stable high-efficiency tumor suppression level, and the drug effect is long-lasting;

2) Controllable drug absorption rate, control the level and fluctuation range of blood drug concentration, and avoid excessive adverse reactions after medication;

3) After a single injection or implantation, it can maintain effective PARP enzyme inhibition for a long period of time, reducing the tedious process of daily medication of common preparations and making it more convenient for clinical medication;

4) Due to the controllable blood drug concentration and its fluctuation range, the safety window is relatively large, and the clinical dose and dosing regimen can be flexibly adjusted during clinical treatment, which is expected to further increase the therapeutic dose and enhance the anti-tumor efficacy.

In order to better illustrate the properties of the olaparib pharmaceutical composition provided by the present invention, the following description is a detailed description of the present invention and does not constitute any limitation to the scope of the present invention.

Description of drawings

Figure 1 shows the release profile of the immediate release talazoparib capsules of Comparative Example 1.

Fig. 2 shows the in vivo drug-time curve in dogs of the immediate-release talazoparib capsule of Comparative Example 1 and the talazoparib in situ gel injection in Example 1.

FIG. 3 shows the release profile of the sustained-release microspheres in Example 2.

Detailed ways

1. Multivesicular liposomes

The multivesicular liposome (Liposomes) provided by the invention is mainly composed of cholesterol and phospholipids, which are closed microvesicles similar to the biological membrane bilayer structure, and are a new type of drug carrier. Liposomes can be divided into 3 classes by structure: unilamellar liposomes (ULV), multilamellar liposomes (MLV) and multivesicular liposomes (MVL), wherein the first two are concentric liposomes, and MVL It belongs to non-concentric liposomes, and MVL is an aggregate composed of non-concentric lipid bimolecular vesicles tightly packed, and is a new type of liposome for drug delivery. After this liposome is loaded with drugs, it is injected into the body to form a drug reservoir, which produces a good sustained-release effect, which can not only reduce the number of medications used by patients, but also improve the compliance of treatment, which has become a research focus of many scholars.

The talazoparib pharmaceutical composition of the present invention can be talazoparib multivesicular liposome form, wherein said talazoparib multivesicular liposome composition comprises active ingredient talazoparib, lipid component (comprising oil and surfactant) and other optional One or a combination of two or more pharmaceutical pH/osmotic pressure regulators; wherein, the talazoparib multivesicular liposome composition contains 0.1-200 parts by weight, preferably 0.5-100 parts by weight, more preferably 1- 50 parts by weight, even more preferably 1-20 parts by weight of the active ingredient talazoparib, 0.1-300 parts by weight, preferably 0.1-200 parts by weight of the lipid component, and optionally 0-10 parts by weight of other pharmaceutically acceptable pH/osmotic pressure regulator

The talazoparib is the only active ingredient loaded into the multivesicular liposomes; the preparation composition may include free talazoparib not encapsulated by multivesicular liposomes, and the amount of free talazoparib not loaded by multivesicular liposomes is generally less than that of the combination 20%, preferably less than 10%, of the total amount of talazoparib in the drug.

The lipid component is selected from at least one amphipathic lipid and/or at least one neutral lipid; the amphipathic lipid includes phosphatidylcholine or phosphatidylglycerol or a corresponding salt or one or more of the above A combination of two or more components; in some instances, the phosphatidylglycerol can be DPPG, and in some instances, the phosphatidylcholine can be selected from DEPC or DOPC or their combination; the neutral lipids include ethyl Glycol esters, squalene, glycerin, triglycerides and propylene glycol esters or mixtures of the above components, etc. In specific examples, triglycerides can be selected from oleic triglycerides or caprylic triglycerides.

In some examples, the composition can also include a lipid membrane fluidity regulator, an osmotic pressure regulator or a pH regulator; the lipid membrane fluidity regulator can be selected from cholesterol or phytosterols, etc.; the pH regulator The agent is selected from non-organic acid, organic acid, non-organic base, and a combination of two or more of organic bases. Specifically, the pH regulator is selected from hydrochloric acid, phosphoric acid, tartaric acid, histidine, butyridine, One or more combinations of trometamol; the pH range of the external phase aqueous solution of the multivesicular liposome of the present invention can be between 4.0-9.0.

The single injection dosage range of the active ingredient talazoparib in the multivesicular liposome composition formulation is 0.1-200 mg, and in some instances, the amount of unencapsulated free talazoparib accounts for 0%-20% of the total amount of talazoparib in the composition. %.

The multivesicular liposome composition provided by the present invention can be administered intravenously, subcutaneously or intramuscularly, preferably subcutaneously.

The preparation method of the multivesicular liposome of the present invention adopts conventional methods in the art, such as adopting the double emulsion method, specifically, it needs to include the following 5 steps: (1) first dissolve the lipid component of the prescription amount in easy Volatile organic solvents (usually chloroform or a mixture of chloroform and ether) form an oil phase, and the talazoparib of the prescribed amount is dissolved in water to form a drug-containing aqueous solution (the first water phase), and then with a suitable oil-water volume ratio (volume ratio) 1:10-12:10, v/v) Mix the drug-containing aqueous solution (the first water phase) with the organic phase of the lipid (oil phase), and prepare a uniform mixture at room temperature by ultrasonic or mechanical shearing for a certain period of time. Water-in-oil (W/O) type colostrum; (2) absorb the formed W/O type colostrum, and inject the second aqueous phase buffer solution according to a certain ratio (volume ratio is 1:10-5:10, v/v ), under the condition of 30°C, mechanically shear and emulsify again to form a stable water-in-oil-in-water (W/O/W) type double emulsion; (3) transfer the double emulsion to the Erlenmeyer flask at a rate of 6L/min Use an inert gas (such as nitrogen) to remove the organic solvent (ether, chloroform, dichloromethane, etc.) in the double emulsion, and nitrogen can be passed into the surface or the nitrogen conduit can be stretched into the bottom of the conical flask to remove the organic solvent; (4) Necessary When the second aqueous phase can be replaced with a physiologically acceptable saline solution (such as 0.9% sodium chloride solution) suitable for storage, it can be concentrated; (5) adjust the drug content and fill according to the content.

Lipids used generally include neutral lipids (commonly used triacylglycerol), phospholipids and cholesterol, etc. Neutral lipids are an important part in the MVL preparation process, otherwise only common liposomes can be obtained. The methods for preparing colostrum include: ultrasound, high-speed dispersion, milk homogenizer, nozzle atomization, etc. In the laboratory, vortex mixers or high-speed dispersers are often used for emulsification.

Different types of media and lipids encapsulated in the prescription will result in different drug release rates, among which the different carbon chain lengths of neutral lipid triglycerides can adjust the drug release rate. In addition, the stirring time, temperature, speed, external water phase volume, nitrogen flow rate, and method of separating free drug during the preparation of MVL will also have a certain impact on its particle size, encapsulation efficiency, encapsulation volume and stability. , adjust the above process conditions to obtain Talazoparib multivesicular liposomes with different release rates.

In the multivesicular liposome provided by the present invention, the release amount within 6 hours is less than 10% or even less than 5% of the total amount of Talazoparib in the preparation; the release amount in 24 hours is less than 30% or even less than 20% of the total amount of Talazoparib; 90% Drug release time > 3 days. After the pharmaceutical composition provided by the present invention is administered by injection, it can quickly reach the blood drug concentration level required for effective anti-tumor PARP enzyme inhibition, and can avoid blood drug concentration fluctuations, and maintain the effective blood drug concentration for several days, even Dozens of days. The effective blood drug concentration can be maintained within the range of 0.2ng/mL-50ng/mL for several to dozens of days, and even the blood drug concentration is greater than 2ng/mL<C<25ng/mL for more than 7 days.

2. Suspension

The talazoparib pharmaceutical composition provided by the present invention can be implemented in the form of talazoparib suspension, so as to realize the release behavior. The suspension may be selected from aqueous medium suspensions or oily medium suspensions.

Talazoparib suspension contains active ingredient talazoparib, oily solvent and/or water for injection, and/or suspension stabilizer, and/or isotonic agent, buffer, etc.;

Wherein, the talazoparib suspension comprises 0.1-200 parts by weight, preferably 0.5-100 parts by weight, more preferably 1-50 parts by weight, even more preferably 1-20 parts by weight of the active ingredient talazoparib, 0-300 parts by weight Oily solvent and/or water for injection, 0.1-500 parts by weight of excipients for adjusting the release rate, and 0-5 parts by weight of isotonic agent and/or buffering agent.

In some embodiments, the oily solvent can be selected from one or a combination of two or more of coconut oil, castor oil, sesame oil, soybean oil, peanut oil, cottonseed oil and other pharmaceutically applicable solvents.

The excipients for adjusting the release rate can be selected from surfactants or polymers, and the surfactants can include polysorbate 80, polysorbate 20, polyoxyethylene castor oil 50, polyoxyethylene castor oil 60, polo One or more combination of sham and polyoxyethylene fatty acid ester, the polymer can include sodium carboxymethyl cellulose, vinyl acetate copolymer, poloxamer, polyethylene glycol, hydroxylactic acid polymer , polyester, polysaccharide, povidone K12/K17, sodium carboxymethylcellulose and poloxamer or a combination of two or more.

The buffering agent may be selected from sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, sodium carbonate, sodium bicarbonate, meglumine, arginine, triethanolamine and citric acid, or a combination of two or more.

The isotonic agent may be selected from one or a combination of two or more of sodium chloride, glucose and mannitol.

The suspension provided by the present invention can be a nanosuspension or a microsuspension, the particle size range of the nanosuspension is 50nm-800nm, and the particle size range of the microsuspension is 1um-18um. It can be prepared by the common homogeneous destruction method in this field, such as first dissolving the suspension stabilizer in water, placing the active drug in the above solution containing the stabilizer, and after preliminary shearing and crushing, at a certain temperature, Circular homogeneous crushing to obtain a suspension with uniform particle size.

The single dose range of the active ingredient talazoparib in the suspension provided by the invention is 0.1-200 mg, preferably 0.5-100 mg; the talazoparib suspension provided by the invention can be administered subcutaneously or intramuscularly, preferably subcutaneously. .

3. In situ gel

In situ gel implant is a research hotspot in the field of sustained-control injection in recent years. It dissolves drugs and polymers in a suitable solvent and injects them locally subcutaneously. At the site of administration, the polymer solidifies under physiological conditions and Form semi-solid or solid drug depots. The in situ gel overcomes the disadvantages of common emulsions, liposomes, microspheres and micelles, and can be used for local administration of lesions, prolonging the release period, reducing dosage and adverse drug reactions, and avoiding surgery on implants Pain during implantation, relatively simple process and other advantages.

The talazoparib pharmaceutical composition provided by the present invention can realize the release behavior in the form of talazoparib in-situ gel system, which is characterized in that the in-situ gel system includes the active ingredient drug talazoparib, a suitable solvent, and a gel for release rate adjustment. glue forming material. Wherein, the talazoparib in situ gel system comprises 0.1-200 parts by weight, preferably 0.5-100 parts by weight, even more preferably 1-50 parts by weight, even more preferably 1-20 parts by weight of the active ingredient talazoparib; 50-2000 parts by weight 0.1-500 parts by weight, preferably 0.5-250 parts by weight, and even more preferably 0.5-100 parts by weight of the release rate-adjusting gel-forming material.

The talazoparib in situ gel system can be prepared in a manner known in the art, specifically, for example, the pharmaceutical 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 gel-forming material for adjusting the release rate of substances, etc., forms a solution, and the solution can directly dissolve the active drug talazoparib, or prepack it 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, the solvent used for dissolving the gel-forming material is quickly absorbed locally, and part of the dissolved drug is also quickly absorbed with the absorption of the solvent, while the gel material in the body encounters an aqueous environment and forms a semi-solid or solid state. Gel, and most of the active drugs dissolved or dispersed in the gel system will be released slowly with the degradation and erosion of the gel, so as to realize the stable absorption of drugs in the body and the maintenance of blood drug concentration.

A suitable solvent in the in situ gel system of the present invention may be selected from N-methylpyrrolidone, polyethylene glycol (mono)methyl ether, glycerol triacetate benzyl benzoate, glycerol furfural, glyceride One or a combination of two or more of formaldehyde, propylene glycol, ethanol, ethylene glycol diethyl ether, benzyl alcohol, dimethyl sulfoxide and other pharmaceutically applicable organic solvents.

The gel-forming material for regulating the release rate includes: polylactic acid (PLA), polylactic-co-glycolic acid (PLGA), sucrose acetate-isobutyrate, fatty acid glycerides, PEGylated PLA/PLGA, One or more combination of triethylene glycol poly(orthoester) polymer and other pharmaceutically applicable sustained and controlled release materials for local injection.

The single dose of the active ingredient talazoparib in the in situ gel system ranges from 0.1-200 mg, preferably 0.5-100 mg, more preferably 1-50 mg, even more preferably 1-20 mg.

The Talazoparib in-situ gel system provided by this method releases less than 20% or even less than 15% of the total amount of Talazoparib in the preparation within 6 hours; the release amount within 24 hours is less than 40% or even less than 30% of the total amount of Talazoparib in the preparation; 90% drug release time > 3 days. After Talazoparib in situ gel system injection administration provided by the present invention, it can quickly reach the blood drug concentration level required for effective anti-tumor PARP enzyme inhibition, and can avoid blood drug concentration fluctuations, and maintain the effective blood drug concentration for several days, even dozens of days. The effective blood drug concentration can be maintained within the range of 0.2ng/mL-50ng/mL for several to dozens of days, and even the blood drug concentration is greater than 2ng/mL<C<25ng/mL for more than 7 days.

The in situ gel system provided by the present invention can be stored for short term in solution state or in the form of pre-filled syringes with drug and solvent.

The in situ gel system provided by the present invention can be administered intravenously, subcutaneously or intramuscularly, preferably subcutaneously and intramuscularly.

4. Microspheres

The microsphere provided by the present invention refers to a tiny spherical entity formed by dissolving or dispersing a drug in a sustained-release polymer material matrix, with a small particle size, belonging to matrix-type skeleton particles. 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 drug release rate of microsphere injection is mainly determined by the polymer delivery system. When the microspheres are injected subcutaneously or intramuscularly, the drug can be slowly released from the microsphere matrix, and the skeleton material can be gradually hydrolyzed and eroded, and the final products of degradation are CO2 _and water, which can be easily absorbed by the body without causing adverse reactions.

The pharmaceutical composition of the release behavior of the present invention can be provided in the form of talazoparib microspheres comprising the active ingredient talazoparib and a polymer material for regulating the release rate. The sustained-release microspheres of the present invention comprise 0.1-200 parts by weight, preferably 0.5-100 parts by weight, even more preferably 1-50 parts by weight, even more preferably 1-20 parts by weight of the active drug talazoparib, and 0.1-500 parts by weight, 0.2-250 parts by weight, even more preferably 1-200 parts by weight of the release rate-adjusting polymer is preferred.

The microsphere preparation provided by the present invention is a dry powder. Before use, it needs to be uniformly suspended with injectable water or other solvents before injection; the other solvents can be selected from the aqueous solution of 0.1wt%-1wt% Tween80, glycerin, polyethylene glycol One or more combinations of glycol, polyethylene glycol methyl ether and other pharmaceutically available solvents for injection that do not affect the stability of microspheres.

The talazoparib sustained-release microspheres can be prepared in a manner known in the art, specifically, after dissolving the active drug talazoparib and the polymer material used for adjusting the release rate in a suitable solvent, spray-drying with an intelligent spray-drying electrostatic collection system Collection and preparation; Talazoparib and suitable release-adjusting polymer materials such as polylactic-co-glycolic acid (PLGA), first dissolved in a solvent such as methylene chloride, slowly injected into the spray at a rate of 0.2ml/min-1ml/min Dry electrostatic system (such as Buchi BUCHI small spray dryer B-290 in Switzerland), the drying temperature is about 40°C-80°C, during the spray drying process, real-time monitoring of microsphere particle size, adjustment of injection rate, spray frequency, heating temperature And the size of the ventilation, after the spray drying is finished, just 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 rate, etc. The physical and chemical properties and yield have a great influence, and the conditions of the above influencing factors can be controlled to obtain the sustained-release microsphere preparation with uniform particle size. The particle size of the sustained-release microspheres provided by the present invention is generally between 0.5 and 20 μm. When the sustained-release microspheres provided by the present invention are locally injected into the human body, the drug will be slowly released along with the degradation and erosion of the polymer matrix for adjusting the release rate, so as to realize the stable absorption of the drug in the body and the maintenance of the blood drug concentration. The polymer matrix material for regulating the release rate includes: polylactic acid (PLA), polylactic acid-glycolic acid copolymer (PLGA), PEGylated PLA/PLGA, chitosan, water-soluble carboxymethyl chitosan , fibroin, poly-β-hydroxybutyrate valerate, polylactide/lactide-polyethylene glycol copolymer blend, poly-β-hydroxybutyrate and polyethylene glycol blend, One or more combinations of polylactic acid/glycolic acid blends and other pharmaceutically applicable sustained and controlled release materials for local injection.

The microsphere system provided by the present invention can be stored for a long time in the form of solid powder.

The sustained-release microsphere preparation provided by the present invention can be administered intravenously, subcutaneously or intramuscularly, preferably subcutaneously and intramuscularly.

Example

The following examples generally describe the preparation methods and/or characterization results of typical compositions of the present invention, and all percentages are by weight unless otherwise indicated. The following examples are specific illustrations of the present invention, but should not be considered as limiting the scope of the present invention. In the following examples, various procedures and methods not described in detail adopt conventional methods well known in the art.

The preparation of embodiment 1 talazoparib gel preparation in situ

After dissolving PLA with N-methylpyrrolidone, and then dissolving the drug talazoparib, the in situ gel injection can be obtained.

The quick-release capsule of comparative example 1 (self-made gelatin quick-release capsule, 25wt% talazoparib tosylate, 33wt% microcrystalline cellulose, 22wt% lactose, 15% mannitol 2wt% micropowder silica gel, 1wt% magnesium stearate After mixing evenly with 2% sodium lauryl sulfate, directly pack into 0# hard capsule and make); Its dissolution measurement adopts the first method device of the dissolution measurement method (Chinese Pharmacopoeia 2010 edition two appendix X C), 37 Under the condition of ℃, use 900mL of hydrochloric acid aqueous solution with pH 1.2 as the release medium, the rotation speed is 75 rpm, operate according to the law, take 6mL of the solution according to the predetermined time point, centrifuge, take the supernatant as the test solution, and measure the release degree.

According to the ultraviolet-visible spectrophotometry (Chinese Pharmacopoeia 2010 edition two appendix IVA), measure absorbance respectively at the wavelength place of 255nm, measure the dissolution rate of capsule.

The release results are shown in Figure 1. More than 80% of the active ingredient talazoparib in the immediate-release capsule is released in about 30 minutes, and basically completely released in 1 hour.

Test Example 1

1 mg equivalent of the talazoparib immediate-release capsules of Comparative Example 1 was administered to fasting beagle dogs (n=3), delivered orally with 25 mL of water, 1 mg equivalent of the talazoparib in situ gel injection of Example 1, at the forelimb medial axillary area After subcutaneous administration, blood was collected at a predetermined time point. The blood sample was centrifuged at 4000 rpm for 10 minutes at 4°C, and the upper layer of plasma was collected for LC-MS blood drug concentration detection. The results are shown in Figure 2. Compared with the _Cmax (15344.5pg/mL) of the capsule preparation, the Cmax of the blood drug concentration provided by the in situ gel preparation is reduced to 8764.1pg/mL, which is about 43% lower; For immediate-release capsules, the in-situ gel preparation can quickly reach the blood concentration required for PARP enzyme inhibition, and can maintain it within the effective blood concentration range for a longer period of time, avoiding the occurrence of excessive drug toxicity, and at the same time, better The enzyme inhibitory effect and anti-tumor effect also provide more space for drug dose climbing and optimal drug efficacy.

Embodiment 2: Preparation of talazoparib microspheres

Dissolve Talazoparib and PLGA in dichloromethane, and inject it into BUCHI B-290 spray-drying static electricity with a drying temperature of 65°C, a spray frequency of 120kHz, and a ventilation rate of 70L/min at an injection rate of 0.2ml/min of 0.5ml/min. Collect the system to prepare microspheres with uniform particle size, and 80% of the microspheres have a particle size of 0.5-10um.

The release test of the talazoparib microsphere of test embodiment 2 embodiment 2

The talazoparib microspheres of Example 2 were incubated in a release medium containing 0.2% Tween 80 in a physiological isotonic PBS solution (pH 7.4), at 37° C., under the condition of 100 r/min, at a predetermined time point, 5 ml of the dissolution medium was taken, After centrifugation at 10,000 rpm for 5 minutes, 20 μl of filtrate from the supernatant was accurately measured and injected into a liquid chromatograph, the chromatogram was recorded, and the drug cumulative release curve was drawn.

The results are shown in Figure 3. The sustained-release microspheres released less than 20% of Talazoparib in 1 hour, about 20% in 120 hours, and continued drug release in 192 hours, with a cumulative release of less than 30%.

Claims (10)

1. Talazoparib pharmaceutical composition, comprising 0.1-200 parts by weight of the active ingredient Talazoparib, 0.1-500 parts by weight of excipients for regulating the release rate, 0-10 parts by weight of small molecule regulators, and 0-2000 parts by weight of pharmaceutical Injectable solvent. 2. Talazoparib pharmaceutical composition according to claim 1, wherein, The adjuvant for adjusting the release rate is selected from pharmaceutical biodegradable polymers, medicinal oils, pharmaceutical surfactants and other pharmaceutical adjuvants (such as sucrose acetate isobutyrate (SAIB ) etc.) or a combination of two or more); Preferably, the pharmaceutical biodegradable polymer is selected from the group consisting of: polylactic acid (PLA), polylactic-co-glycolic acid (PLGA), polyorthoesters, sucrose acetate-isobutyrate, fatty acid glycerol Ester, PEGylated PLA/PLGA, Triethylene glycol poly(orthoester) polymer, Chitosan, Water soluble carboxymethyl chitosan, Fibroin, Poly-beta-hydroxybutyrate valerate esters, polylactide/lactide-polyethylene glycol copolymers and/or blends thereof, poly-β-hydroxybutyrate and polyethylene glycol blends, and polylactic acid/glycolic acid blends one or a combination of two or more, Preferably, the pharmaceutical surfactant is selected from: phospholipids for injection, Tween 20, Tween 80, Cremophor EL, Solutol HS 15, polysorbate 80, polysorbate 20, polyoxyethylene castor oil , polyoxyethylene fatty acid ester, poloxamer 188, phosphatidylcholine (such as DEPC or DOPC or their combination), phosphatidylglycerol (such as DPPG) and other pharmaceutically acceptable surfactants or a combination of two or more, Preferably, the medicinal oil is selected from: glycerin, cholesterol, propylene glycol ester, ethylene glycol ester, squalene, stearic acid, olive oil, soybean oil, coconut oil, castor oil, sesame oil, peanut oil, cottonseed Oil triglycerides (such as oleic acid triglyceride or caprylic acid triglyceride) and other medicinal oils (glycerol oleic acid or its mixture with phospholipids, etc.) and one or more combinations of corresponding salts; and /or Wherein, the small molecule regulator is selected from the group consisting of: acetic acid, anhydrous citric acid, ascorbic acid, calcium chloride, benzocresol, edetate calcium disodium, edetate sodium, glycine, histidine, hydrochloric acid, Lactic acid, lactose monohydrate, magnesium chloride, mannitol, methanesulfonic acid, methionine, phenol, phosphoric acid, anhydrous dipotassium hydrogen, sodium acetate, sodium ascorbate, sodium bicarbonate, sodium bisulfite, 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 bicarbonate, meglumine, protamine, propylparaben One or a combination of two or more of esters, cholesterol, phytosterols, arginine, triethanolamine, glucose, sorbitol, sucrose, tartaric acid, tromethamine, zinc acetate, zinc chloride, and glucose; and/or The pharmaceutical injectable solvent is selected from: water, benzyl alcohol, chlorobutanol, dimethyl sulfoxide, methylpyrrolidone, propylene glycol, polyethylene glycol (mono) methyl ether, glyceryl triacetate benzyl benzoate, One or a combination of two or more of glycerol furfural, glycerin formal, propylene glycol, ethanol, ethylene glycol diethyl ether and other pharmaceutically acceptable injection solvents. 3. Talazoparib pharmaceutical composition according to claim 1 or 2, wherein, described Talazoparib pharmaceutical composition is after administration, in aqueous medium, under 37 ℃ of conditions, release amount is less than 10% of Talazoparib total amount within 6 hours. %, even less than 5%; 24h release is less than 30% of the total amount of Talazoparib, even less than 20%; 90% drug release time> 3 days, even greater than 7 days, greater than 14 days or greater than 30 days. 4. according to the Talazoparib pharmaceutical composition described in any one in claim 1 to 3, wherein, described Talazoparib pharmaceutical composition is after administration, can regulate the absorption behavior of medicine by controllable release behavior, maintains in effectively inhibiting The blood drug concentration required by PARP enzyme is several days, even dozens of days, for example, the effective blood drug concentration can be maintained in the range of 0.2ng/mL-50ng/mL for several days to dozens of days, even the blood drug concentration is greater than 2ng /mL<C<25ng/mL is maintained for more than 7 days, and then maintained at an effective PARP enzyme inhibition level for several days, even dozens of days, increasing the anti-tumor efficacy of the drug. 5. The Talazoparib pharmaceutical composition according to any one of claims 1 to 4, wherein the Talazoparib pharmaceutical composition is selected from suspensions for injection or implantation, oil injection preparations, sustained-release microspheres, Implant gel, multivesicular liposomes and other applicable sustained-release local injection delivery systems (such as SABER delivery system and CamurusFluidCrystal injection system). 6. Talazoparib pharmaceutical composition according to any one of claims 1 to 4, wherein, The talazoparib pharmaceutical composition is talazoparib multivesicular liposome, Preferably, the talazoparib multivesicular liposomes comprise 0.1-200 parts by weight, preferably 0.5-100 parts by weight, more preferably 1-50 parts by weight of talazoparib; 0.1-300 parts by weight, preferably 0.1-200 parts by weight of lipids composition; and optional other pharmaceutically acceptable pH/osmotic pressure regulators of 0-10 parts by weight; Preferably, the talazoparib multivesicular liposomes include free talazoparib not encapsulated by multivesicular liposomes, and the amount of free talazoparib not loaded by multivesicular liposomes is generally less than 20% of the total amount of talazoparib in the composition, preferably less than 10%; Preferably, the lipid component is selected from at least one amphipathic lipid and/or at least one neutral lipid; Preferably, the amphiphilic lipid comprises phosphatidylcholine or phosphatidylglycerol or a corresponding salt or a combination of two or more of the above components; Preferably, the phosphatidylglycerol is DPPG, and the phosphatidylcholine is selected from DEPC or DOPC or a combination thereof; Preferably, the neutral lipids include ethylene glycol esters, squalene, glycerin, triglycerides and propylene glycol esters or a mixture of two or more of the above components; Preferably, the triglyceride is selected from oleic triglyceride or caprylic triglyceride; Preferably, the talazoparib multivesicular liposome further includes a lipid membrane fluidity regulator, an osmotic pressure regulator or a pH regulator; Preferably, the lipid membrane fluidity regulator is selected from cholesterol or phytosterols; The pH regulator is selected from non-organic acid, organic acid, non-organic base, one or more combinations of organic bases, for example, the pH regulator is selected from hydrochloric acid, phosphoric acid, tartaric acid, histidine, butylamine Acid, trometamol or a combination of two or more; Preferably, the pH range of the aqueous solution of the external phase of the multivesicular liposomes can be between 4.0-9.0; The multivesicular liposome of talazoparib is preferably administered by intravenous, subcutaneous or intramuscular injection, more preferably subcutaneous injection; Preferably, the release amount of the talazoparib multivesicular liposomes within 6 hours is less than 10%, or even less than 5%, of the total amount of talazoparib in the preparation; the amount of release in 24 hours is less than 30%, or even less than 20%, of the total amount of talazoparib; 90% Drug release time > 3 days. 7. Talazoparib pharmaceutical composition according to any one of claims 1 to 4, wherein, Described Talazoparib pharmaceutical composition is Talazoparib suspension, Preferably, the talazoparib suspension comprises 0.1-200 parts by weight, preferably 0.5-100 parts by weight, more preferably 1-50 parts by weight, more preferably 1-20 parts by weight of talazoparib, 0-300 parts by weight of an oily solvent and /or water for injection, 0.1-500 parts by weight of excipients for adjusting the release rate, 0-5 parts by weight of isotonic agent and/or buffer; Preferably, the oily solvent is one or a combination of two or more selected from coconut oil, castor oil, sesame oil, soybean oil, peanut oil, cottonseed oil and other pharmaceutically applicable solvents; Preferably, the excipient for adjusting the release rate is selected from surfactants or polymers, for example, the surfactant is selected from polysorbate 80, polysorbate 20, polyoxyethylene castor oil 50, poly One or more combinations of oxyethylene castor oil 60, poloxamer and polyoxyethylene fatty acid ester; The polymer is selected from sodium carboxymethylcellulose, vinyl acetate copolymer, poloxamer, polyethylene glycol, hydroxylactic acid polymer, polyester, polysaccharide, povidone K12/K17, carboxymethyl One or a combination of two or more of sodium cellulose base and poloxamer; Preferably, the buffering agent is selected from sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, sodium carbonate, sodium bicarbonate, meglumine, arginine One or a combination of two or more of , triethanolamine and citric acid; Preferably, the isotonic agent is one or a combination of two or more selected from sodium chloride, glucose and mannitol; Preferably, the Talazoparib suspension is a nanosuspension or a microsuspension, the particle size range of the nanosuspension is preferably 50nm-800nm, and the particle size range of the microsuspension is preferably 1um-18um. 8. The Talazoparib pharmaceutical composition according to any one of claims 1 to 4, wherein, The talazoparib pharmaceutical composition is a talazoparib in situ gel system, Preferably, the talazoparib in situ gel system comprises 0.1-200 parts by weight, preferably 0.5-100 parts by weight, more preferably 1-50 parts by weight, even more preferably 1-20 parts by weight of talazoparib; 50-2000 parts by weight, Preferably 100-1000 parts by weight of a solvent; 0.1-500 parts by weight, preferably 0.5-250 parts by weight, even more preferably 1-100 parts by weight of a release rate-adjusting gel-forming material; Preferably, the solvent is selected from N-methylpyrrolidone, polyethylene glycol (mono) methyl ether, glyceryl triacetate benzyl benzoate, glycerol furfural, glycerin formal, propylene glycol, ethanol, ethylene glycol diol One or a combination of two or more of ether, benzyl alcohol, dimethyl sulfoxide and other pharmaceutically applicable pharmaceutical injection solvents; Preferably, the gel-forming material for adjusting the release rate is selected from the group consisting of: polylactic acid (PLA), polylactic-co-glycolic acid (PLGA), sucrose acetate-isobutyrate, fatty acid glycerides, pegylated PLA/PLGA, triethylene glycol poly(orthoester) polymer, and other pharmaceutically applicable sustained-release materials for local injection or a combination of two or more; Preferably, the single dose of talazoparib in the in situ gel system ranges from 0.1-200 mg, preferably 0.5-100 mg, more preferably 1-50 mg, even more preferably 1-20 mg; Preferably, the Talazoparib in-situ gel system releases less than 20%, or even less than 15%, of the total amount of Talazoparib in the formulation 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; Preferably, the in situ gel system is stored as a solution for short-term storage, or as a pre-filled syringe of drug and solvent; Preferably, the in situ gel system is administered by intravenous, subcutaneous or intramuscular injection, preferably subcutaneous and intramuscular injection. 9. Talazoparib pharmaceutical composition according to any one of claims 1 to 4, wherein, The Talazoparib pharmaceutical composition is sustained-release microspheres, Preferably, the sustained-release microspheres comprise 0.1-200 parts by weight, preferably 0.5-100 parts by weight, even more preferably 1-50 parts by weight, even more preferably 1-20 parts by weight of talazoparib, and 0.1-500 parts by weight, Preferably 0.2-250 parts by weight, even more preferably 1-200 parts by weight of the release rate modifying polymer; Preferably, the sustained-release microspheres are dry powders, which need to be uniformly suspended with injectable water or other solvents before injection; The other solvents are selected from the aqueous solution of 0.1wt%-1wt% Tween80, glycerin, polyethylene glycol, polyethylene glycol methyl ether and other pharmaceutically available injection solvents that do not affect the stability of the microspheres. One or a combination of two or more; Preferably, the particle size distribution of the slow-release microspheres is between 0.5 and 20 μm; Preferably, the release rate regulating polymer is selected from polylactic acid (PLA), polylactic-co-glycolic acid (PLGA), PEGylated PLA/PLGA, chitosan, water-soluble carboxymethyl shell Polysaccharide, fibroin, poly-β-hydroxybutyrate valerate, polylactide/lactide-polyethylene glycol copolymer blend, poly-β-hydroxybutyrate blended with polyethylene glycol One or more combinations of materials, polylactic acid/glycolic acid blends and other pharmaceutically applicable sustained-release materials for local injection; Preferably, the sustained-release microspheres are administered through intravenous, subcutaneous or intramuscular injection, preferably subcutaneous and intramuscular injection. 10. Use of the Talazoparib pharmaceutical composition according to any one of claims 1 to 9 in the preparation of medicines for treating and/or preventing tumors with DNA repair function defects.