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WO2025124422A1 - In-situ subcutaneous implantable female hormone modulation composition, preparation method therefor, and use thereof - Google Patents

In-situ subcutaneous implantable female hormone modulation composition, preparation method therefor, and use thereof Download PDF

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Publication number
WO2025124422A1
WO2025124422A1 PCT/CN2024/138415 CN2024138415W WO2025124422A1 WO 2025124422 A1 WO2025124422 A1 WO 2025124422A1 CN 2024138415 W CN2024138415 W CN 2024138415W WO 2025124422 A1 WO2025124422 A1 WO 2025124422A1
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Prior art keywords
composition
dienogest
lactide
thermoplastic polymer
glycolide
Prior art date
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Pending
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PCT/CN2024/138415
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French (fr)
Chinese (zh)
Inventor
吕刚
刘阳
薛菲
杨洪宝
李超男
邹爱峰
杨方龙
王思勤
金磊
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Changchun Genescience Pharmaceutical Co Ltd
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Changchun Genescience Pharmaceutical Co Ltd
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Publication of WO2025124422A1 publication Critical patent/WO2025124422A1/en
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Classifications

    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/567—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in position 17 alpha, e.g. mestranol, norethandrolone
    • 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
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • 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
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/34—Gestagens

Definitions

  • the invention belongs to the field of pharmaceutical preparations, and relates to an in situ subcutaneously implanted female hormone regulating pharmaceutical composition, a preparation method and an application thereof.
  • Female hormones and their agonists/antagonists are commonly used drugs for these female diseases. Indications include breast cancer, endometriosis, hormone replacement, etc.
  • Common drugs include:
  • Fulvestrant is suitable for the treatment of estrogen receptor-positive metastatic breast cancer in postmenopausal women whose disease worsens after anti-estrogen treatment.
  • the ingredients in the Fulvestrant injection currently on the market include ethanol, benzyl alcohol, benzyl benzoate, castor oil, etc., and there are many contraindications and adverse reactions when using it.
  • ethanol is irritating and prone to allergies, so patients with ethanol allergies cannot use it; the use of benzyl benzoate may cause systemic allergic reactions, central nervous system stimulation reactions and spasms; benzyl alcohol injection must be marked as prohibited for intramuscular injection in children, and there are many adverse reactions.
  • Castor oil has a complex composition and is prone to allergic reactions. Therefore, it is necessary to develop a formulation that can remove the above-mentioned adverse reaction ingredients in the prescription, improve the safety of medication, and have obvious clinical advantages.
  • Estradiol is a female hormone that regulates many physiological processes in the body. It is mainly used to improve menopausal symptoms (such as hot flashes and vulvovaginal changes) and prevent osteoporosis in menopausal women, and requires long-term medication.
  • Dienogest is a mixed progestin with the dual properties of 19-nortestosterone derivatives and progesterone derivatives. It can relieve endometriosis dysmenorrhea and shrink ovarian endometriosis cysts. The effect of shrinking ectopic cysts is more significant as the medication time is prolonged. Dienogest can be used for oral contraceptives, hormone replacement therapy for estrogen deficiency and the treatment of endometriosis. The currently marketed dienogest preparations are single or compound tablets with a dosing cycle of once a day. It is best to take it at the same time every day. Therefore, poor compliance may occur due to the patient's unwillingness or failure to take the oral medication as prescribed. Endometriosis is a hormone-dependent disease. In order to effectively control the progression of the disease and prevent recurrence, dienogest needs to be taken continuously for a long time.
  • female hormone regulating drugs are looking forward to the development of dosage forms that reduce the frequency of dosing and have stable long-acting release, so as to achieve stable release of drugs, improve drug bioavailability and efficacy, reduce adverse reactions and drug usage, and better improve medication compliance.
  • the present invention provides a composition comprising: (a) a biodegradable thermoplastic polymer; (b) a polar aprotic organic liquid; and (c) dienogest.
  • the biodegradable thermoplastic polymer may be present in a suitable amount, provided that the biodegradable thermoplastic polymer is at least substantially insoluble in aqueous media or body fluids.
  • the biodegradable thermoplastic polymer is selected from one or more combinations of polyglycolide (PGA), polylactide (PLA), polycaprolactone (PCL) and poly(lactide-co-glycolide) (PLGA), preferably polylactide and/or poly(lactide-co-glycolide).
  • the mass ratio of the two is (1-7): 1, such as (1.3-6): 1, and exemplarily 1.5: 1, 2: 1, 3: 1, 3.5: 1, 4: 1, 4.5: 1, 5: 1 or 5.5: 1.
  • the biodegradable thermoplastic polymer is selected from polylactide and poly(lactide-co-glycolide), and the mass ratio of the two is (1-7): 1, such as (1.3-6): 1, and exemplarily 1.5: 1, 2: 1, 3: 1, 3.5: 1, 4: 1, 4.5: 1, 5: 1 or 5.5: 1.
  • the polylactide is carboxyl or ester terminated.
  • the lactide-co-glycolide copolymer is carboxyl or ester terminated.
  • the molar ratio of lactide to glycolide in the lactide-glycolide copolymer is (50-85):(50-15), for example, 50:50, 75:25, 85:15, etc.
  • the biodegradable thermoplastic polymer accounts for 10 wt.% to 95 wt.%, preferably 20 wt.% to 70 wt.%, and also preferably 30 wt.% to 60 wt.%.
  • the biodegradable thermoplastic polymer accounts for 15 wt.%, 25 wt.%, 35 wt.%, 36.6 wt.%, 38.1 wt.%, 40 wt.%, 41.1 wt.%, 42.5 wt.%, 42.8 wt.%, 43.75 wt.%, 45 wt.%, 50 wt.%, 55 wt.%, 65 wt.%, 75 wt.%, 80 wt.%, 85 wt.%, 90 wt.% of the composition.
  • the average molecular weight of the biodegradable thermoplastic polymer is from 10,000 Daltons (Da) to 45,000 Daltons, preferably from about 15,000 Daltons to about 30,000 Daltons.
  • the biodegradable thermoplastic polymer is selected from carboxyl-terminated lactide-glycolide copolymers, and the molar ratio of lactide to glycolide is 50:50, 75:25 or 85:15.
  • the biodegradable thermoplastic polymer is selected from ester-terminated lactide-glycolide copolymers, and the molar ratio of lactide to glycolide is 50:50, 75:25 or 85:15.
  • the biodegradable thermoplastic polymer is selected from carboxyl-terminated polylactide.
  • the biodegradable thermoplastic polymer is selected from carboxyl-terminated polylactide and ester-terminated lactide-glycolide copolymer.
  • the polar aprotic organic liquid is selected from biocompatible polar aprotic organic liquids, for example, selected from N-methylpyrrolidone, 2-pyrrolidone, N,N-dimethylformamide, dimethyl sulfoxide, propylene carbonate, caprolactam, triacetin or a combination of two or more of any of the foregoing liquids; preferably dimethyl sulfoxide and/or N-methylpyrrolidone.
  • the polar aprotic organic liquid accounts for about 10wt.% to about 90wt.% of the composition, preferably about 30wt.% to about 70wt.%.
  • the polar aprotic organic liquid accounts for 15wt.%, 25wt.%, 35wt.%, 36.6wt.%, 40wt.%, 43.4wt.%, 45wt.%, 50wt.%, 55wt.%, 65wt.%, 75wt.%, 80wt.%, 85wt.% of the composition.
  • the mass ratio of the biodegradable thermoplastic polymer to the polar aprotic organic liquid is 0.5-2.0, such as 0.5-1.5, 0.5-1.1, 0.5-1.0, 0.5-0.9 or 0.6-0.88, exemplified by 0.7, 0.75, 0.8, 0.84, 0.85, 1.0.
  • the mass percentage of the dienogest in the composition is not less than 0.001wt.%, and its upper limit is the limit of the dispersibility of the dienogest in the composition.
  • the mass percentage of the dienogest is about 0.5wt.% to about 50wt.%, more preferably about 1wt.% to about 30wt.%.
  • the mass percentage of the dienogest is 0.1wt.%, 1.5wt.%, 2wt.%, 3wt.%, 4wt.%, 5wt.%, 6wt.%, 7wt.%, 8wt.%, 9wt.%, 10wt.%, 11wt.%, 12wt.%, 13wt.%, 14wt.%, 15wt.%, 16wt.%, 17wt.%, 18wt.%, 19wt.%, 20wt.%, 25wt.%, 35wt.%, 40wt.%, 45wt.%.
  • the composition comprises 30 wt.% to 60 wt.% of polylactide and/or lactide-glycolide copolymer, 30 wt.% to 70 wt.% of N-methylpyrrolidone or dimethyl sulfoxide, and 1 wt.% to 30 wt.% of dienogest.
  • composition is selected from the following compositions of any formula:
  • Formula 1 43.75wt% of carboxyl-terminated lactide-glycolide copolymer (molar ratio of lactide to glycolide 50:50), 50wt% of N-methylpyrrolidone, and 6.25wt% of dienogest;
  • Formula 2 43.75wt% of ester-terminated lactide-glycolide copolymer (molar ratio of lactide to glycolide 50:50), 50wt% of N-methylpyrrolidone, and 6.25wt% of dienogest;
  • Formulation 3 40 wt% of carboxyl-terminated lactide-glycolide copolymer (molar ratio of lactide to glycolide 75:25), 47.5 wt% of N-methylpyrrolidone, and 12.5 wt% of dienogest;
  • Formulation 4 40 wt% of ester-terminated lactide-glycolide copolymer (molar ratio of lactide to glycolide 75:25), 47.5 wt% of N-methylpyrrolidone, and 12.5 wt% of dienogest;
  • Formula 5 38.1 wt% carboxyl-terminated polylactide, 45.2 wt% N-methylpyrrolidone, 16.7 wt% dienogest
  • Formulation 6 41.1 wt% of ester-terminated lactide-glycolide copolymer (molar ratio of lactide to glycolide 50:50), 48.9 wt% of N-methylpyrrolidone, and 10.0 wt% of dienogest;
  • Formulation 7 38.1 wt% of carboxyl-terminated lactide-glycolide copolymer (molar ratio of lactide to glycolide 50:50), 45.2 wt% of N-methylpyrrolidone, and 16.7 wt% of dienogest;
  • Formulation 8 38.1 wt% of carboxyl-terminated lactide-glycolide copolymer (molar ratio of lactide to glycolide 75:25), 45.2 wt% of N-methylpyrrolidone, and 16.7 wt% of dienogest;
  • Formulation 9 38.1 wt% of ester-terminated lactide-glycolide copolymer (molar ratio of lactide to glycolide 50:50), 45.2 wt% of N-methylpyrrolidone, and 16.7 wt% of dienogest;
  • Formulation 10 41.1 wt% of ester-terminated lactide-glycolide copolymer (molar ratio of lactide to glycolide 50:50), 48.9 wt% of N-methylpyrrolidone, and 10.0 wt% of dienogest;
  • Formulation 11 42.8 wt % of ester-terminated lactide-glycolide copolymer (molar ratio of lactide to glycolide 50:50), 50.9 wt % of N-methylpyrrolidone, and 6.3 wt % of dienogest;
  • Formulation 12 16.7 wt % of ester-terminated lactide-glycolide copolymer (molar ratio of lactide to glycolide 50:50), 66.6 wt % of N-methylpyrrolidone, and 16.7 wt % of dienogest;
  • Formulation 13 36.6wt% of carboxyl-terminated polylactide, 43.4wt% of N-methylpyrrolidone, and 20.0wt% of dienogest;
  • Formulation 14 36.6wt% of carboxyl-terminated polylactide, 43.4wt% of dimethyl sulfoxide, and 20.0wt% of dienogest;
  • Formulation 15 29.3 wt% of carboxyl-terminated polylactide, 7.3 wt% of ester-terminated lactide-glycolide copolymer (molar ratio of lactide to glycolide 75:25), 43.4 wt% of dimethyl sulfoxide, and 20.0 wt% of dienogest;
  • Formulation 16 22.0 wt% of carboxyl-terminated polylactide, 14.6 wt% of ester-terminated lactide-glycolide copolymer (molar ratio of lactide to glycolide 75:25), 43.4 wt% of dimethyl sulfoxide, and 20.0 wt% of dienogest.
  • the volume of the composition is about 0.20 mL to about 2.0 mL, preferably about 0.20 mL to about 1.0 mL, and more preferably about 0.20 mL to about 0.5 mL.
  • the composition is a flowable composition, for example a gel.
  • the composition is a stable sustained-release composition, which is a subcutaneous injection durable sterile composition suitable for forming an in situ solid, semisolid or gel implant in the body of an administration subject.
  • the biodegradable thermoplastic polymer, polar aprotic organic liquid, and dienogest of the composition are mixed and placed, or the mixture of the biodegradable thermoplastic polymer and polar aprotic organic liquid and dienogest are placed separately.
  • the composition releases dienogest, and dienogest can take effect immediately but without obvious burst release.
  • the composition can provide a stable plasma drug concentration after implantation and provide a plasma concentration of dienogest of C min -C max of the tablet after 1-84 days of administration, without the need for additional oral preparations.
  • the release time of the dienogest can last for 1-6 months, and 50-300 mg of dienogest is administered to a patient in need of the composition each time.
  • the composition has good physical and chemical stability, for example, it can be stored at 2-8° C. for 6-24 months, preferably for 12 months, and more preferably for 24 months.
  • the present invention also provides the use of the above composition in preparing therapeutic drug preparations or medical devices.
  • the pharmaceutical preparation and medical device are used to treat endometriosis.
  • the pharmaceutical preparation may be an injection.
  • the medical device is a kit.
  • the invention also provides a kit, comprising the composition.
  • the kit further comprises a container for containing the composition, for example, a first container and a second container, or a single container such as a prefilled syringe.
  • the first container is used to contain the dienogest;
  • the second container is used to contain a biodegradable thermoplastic polymer and a polar aprotic organic liquid, preferably a mixture of N-methylpyrrolidone and lactide-co-glycolide, N-methylpyrrolidone and polylactide, dimethyl sulfoxide and polylactide and lactide-co-glycolide.
  • the first container can be connected to the second container.
  • the present invention also provides a method for preparing the composition, comprising mixing the mixture of the biodegradable thermoplastic polymer and the polar aprotic organic liquid with dienogest before administration, for example mixing up to 300 times, preferably mixing 250 times, more preferably mixing 200 times.
  • the present invention also provides a method for preparing the composition, comprising mixing a biodegradable thermoplastic polymer, a polar aprotic organic liquid and dienogest before administration.
  • the present invention also provides a method for treating diseases caused by hormone imbalance in women, comprising administering a therapeutically effective amount of the above composition to a patient in need;
  • the disease is endometriosis.
  • plurality refers to more than two, for example, two, three or more.
  • patient refers to any animal including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses or primates, and most preferably humans.
  • terapéuticaally effective amount refers to the amount of an active compound or drug that elicits the biological or medical response that a researcher, veterinarian, physician or other clinician is seeking in a tissue, system, animal, individual or human, and includes one or more of the following: (1) Preventing disease: e.g., preventing a disease, disorder or condition in an individual who is susceptible to the disease, disorder or condition but does not yet experience or develop the pathology or symptoms of the disease. (2) Inhibiting disease: e.g., inhibiting a disease, disorder or condition (i.e., preventing further development of the pathology and/or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder or condition. (3) Alleviating disease: e.g., alleviating a disease, disorder or condition (i.e., reversing the pathology and/or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder or condition.
  • Preventing disease e.g., preventing a disease,
  • the pharmaceutical composition provided by the present invention can release dienogest in a long-term manner, and can achieve at least one of the following effects: (a) a relatively small volume of injection; (b) good tissue tolerance at the injection site; (c) better release kinetics with minimal burst release; (d) extended drug release duration at a lower injection frequency; (e) good stability; and (f) a simple preparation process, relatively low difficulty in aseptic control, and easy industrialization.
  • FIG1 is a pharmacokinetic curve diagram of an estradiol composition
  • FIG. 2 is a pharmacokinetic curve of the dienogest composition in rats.
  • FIG. 3 is a pharmacokinetic curve of the dienogest composition in beagle dogs.
  • FIG. 4 is a graph showing changes in endometrial volume before and after administration of the dienogest composition to rats.
  • FIG. 5 is a graph showing changes in endometrial weight before and after administration of the dienogest composition to rats.
  • FIG6 is a graph showing the body weight change trend of rats before and after administration of the dienogest composition.
  • lactide-glycolide copolymer (5050) represents a lactide-glycolide copolymer in which the molar ratio of lactide to glycolide is 50:50.
  • lactide-co-glycolide copolymer is dissolved in a polar aprotic organic liquid until the polymer solution is clear and transparent, and the prescribed amount of fulvestrant is added to the polymer solution and mixed until the active ingredient is evenly distributed.
  • the purpose of this example is to prepare a long-acting composition of fulvestrant and investigate the effects of different PLGA models, end groups and solvents on the preparation. However, it was found that after adding fulvestrant, the solution was rapidly separated and the preparation existed in two phases, and a uniform preparation could not be prepared.
  • lactide-co-glycolide copolymer was dissolved in NMP until the polymer solution was clear and transparent, and the prescribed amount of estradiol was added to the above polymer solution and mixed until the active ingredients were evenly distributed.
  • Test sample 1 Estradiol gel was prepared according to Preparation 5, with a specification of 0.8 mg/ml.
  • Test sample 2 Estradiol gel was prepared according to Preparation 6, with a specification of 0.8 mg/ml.
  • mice Sprague Dawley rats (SPF grade), male SD rats, aged 6-8 weeks, weighing 200-220 g, 6 rats in each group, original source ... male SD rats, male SD rats, male SD rats, male SD rats, male SD rats, male SD rats, male SD rats, male SD rats, male SD rats, male SD rats, male SD rats, male SD rats, male SD rats, male SD rats, male SD rats, male SD rats, male SD rats, male SD rats, male SD rats, male SD rats, male SD rats, male SD rats, male SD rats, male SD rats, male SD rats, male SD rats, male SD rats, male SD rats, male SD rats, male SD rats, male SD rats, male SD rats, male SD rats, male SD rats, male SD rats, male SD rats, male SD rats, male SD rats, male SD rats, male SD rats, male SD rats, male SD rats, male SD rats, male SD rats, male SD rats, male SD rats, male SD rats, male SD rats, male SD rats, male SD rats, male SD rats, male SD rats, male SD rats, male
  • the oral bioavailability of the reference substance is 5%
  • Group 1 Subcutaneous injection, blood samples were collected at 0h (before administration) and 0.5h, 1h, 2h, 4h, 6h, 8h, 1d, 7d, 14d, 30d, 45d, and 60d after administration to measure the blood concentration of estradiol.
  • Group 2 Subcutaneous injection, blood samples were collected at 0h (before administration) and 0.5h, 1h, 2h, 4h, 6h, 8h, 1d, 7d, 14d, 30d, and 36d after administration to measure the blood concentration of estradiol.
  • Group 3 Gavage, blood samples were collected at 0h (before administration) and 0.5h, 1h, 2h, 4h, 6h, 8h, and 24h after administration to measure the blood concentration of estradiol. The collected blood samples were placed in heparin anticoagulation blood collection tubes and centrifuged to separate plasma (centrifugal force 4000rpm, centrifugation 10min, 2-8°C). The plasma samples were stored in a -40°C refrigerator before delivery. The drug concentration in plasma was determined by HPLC-MS/MS.
  • the burst release of the long-acting composition of estradiol is obvious
  • the Cmax of test sample 1 and test sample 2 is 83.30 ng/ml and 100.36 ng/ml
  • the Cmax of the control tablet is 0.11 ng/ml
  • the burst release of the gel is 757-912 times that of the tablet. Dose dumping may bring safety problems. Therefore, for long-acting preparations, safety issues must be highly valued.
  • the dienogest compositions prepared in Table 6 are all uniform transparent or white to milky white preparations.
  • the preparations prepared in Table 7 were filled into prefilled syringes, and the samples were placed at 2-8°C for 6 months to investigate the changes in dienogest content, related substances, and molecular weight of the lactide-co-glycolide copolymer.
  • the dienogest sample has good stability. After being placed at 2-8°C for 6 months, there is no significant change in the dienogest content, related substances, and molecular weight of the lactide-co-glycolide copolymer.
  • the initial release depends on the polymer concentration (the higher the concentration, the lower the burst release of dienogest), the drug loading (the higher the drug loading, the lower the burst release) and the ratio of lactide to glycolide (the higher the ratio of lactide, the lower the burst release), and the difference between the carboxyl end group and the ester end group has little effect on the release.
  • the drug loading of 16.7% is the preferred formulation.
  • Test drugs Preparations 13, 14, and 15.
  • mice Sprague Dawley rats (SPF grade), female SD rats, aged 8-9 weeks, weighing 200-220 g, 7 rats in each group.
  • test group i.e., preparations 13-15
  • blood samples were collected at 0h, 0.5h, 1h, 2h, 4h, 6h, 8h, 1d, 7d, 14d, 21d, 28d, 35d, and 42d to measure the blood concentration of dienogest.
  • Control group day 1: 0, 0.5, 1, 1.5, 2, 4, 6, 8h; day 2-4: 0h, 0.5h; day 5: 0, 0.5, 1, 1.5, 2, 4, 6, 8, 24h; blood samples were collected to measure the blood concentration of dienogest.
  • the blood collection time window for blood collection points within 1 hour is ⁇ 1 minute, and the blood collection time window for other time points is ⁇ 5%.
  • Plasma 0.4 mL of whole blood was collected from the rat jugular vein at each sampling time point.
  • the EP tube was stored upright at 2-8°C and centrifuged (4000 rpm, 2-8°C, centrifuged for 10 min) to obtain plasma, which was divided into 2 portions, 100 ⁇ L + backup.
  • the separated plasma was stored at -40°C.
  • the drug concentration in plasma was determined by HPLC-MS/MS.
  • Table 16 shows that the control group was continuously administered with dienogest tablets for 5 days, and the C min -C max of the tablets ranged from 0.35 to 385.14 ng/ml.
  • the data showed that the initial burst release C max of the three groups of dienogest injectable compositions tested (i.e., preparations 13-15) was 118.54 to 136.04 ng/ml, all lower than the C max of the tablets, indicating that the dienogest composition preparation has good safety.
  • Table 15 and Figure 2 show that in the test group of preparations 13-15, at 35 days, all the test rats had quantifiable concentrations of dienogest in their bodies. During the entire administration cycle of 42 days, the plasma concentration of the dienogest injectable composition was between the C min -C max of the tablet, which can meet the long-term release of one month. Among them, it was found that the carboxyl end-capping and ester end-capping of the copolymer would affect the bioavailability AUC last of the preparation.
  • the AUC last of preparations 13 and 14 was compared, and the results showed that the AUC last of the carboxyl end-capped copolymer preparation was significantly higher than that of the ester end-capped copolymer preparation, so the carboxyl end-capped copolymer is preferred.
  • the molar ratio of lactide affects the release cycle of the preparation (release cycle evaluation index: T 1/2 ). Considering the release cycle of one month, the carboxyl end-capping of the lactide-glycolide copolymer (5050) is preferred.
  • the prescribed amount of polylactide and lactide-co-glycolide copolymer (if any) was weighed, DMSO/NMP was added to the small tank of a centrifugal defoamer, mixed at 2200 rpm for 5 to 10 min, the prescribed amount of dienogest was added, and mixed at 2200 rpm for 10 to 20 min to obtain preparations 19-22.
  • Test drugs Preparations 19, 20, 21, and 22.
  • mice Beagle dogs, female, aged 8-11 weeks, weighing 8-14 kg, 6 dogs in each group.
  • test group i.e., preparations 19-22
  • blood samples were collected at 0, 0.5h, 1h, 2h, 4h, 6h, 8h, 1d, 7d, 14d, 21d, 28d, 56d, and 84d to measure the blood concentration of dienogest.
  • Control group day 1: 0, 0.5, 1, 2, 4, 6, 8h; day 2: 0h, 0.5h; day 3: 0, 0.25, 0.5, 1, 1.5, 2, 4, 6, 8h, 12h, 24h; blood samples were collected to measure the blood concentration of dienogest.
  • the blood collection time window for blood collection points within 1 hour is ⁇ 1 minute, and the blood collection time window for other time points is ⁇ 5%.
  • Plasma 1 mL of whole blood was collected from the dog's head vein at each sampling time point.
  • the EP tube was stored upright at 2-8°C and centrifuged (4000 rpm, 2-8°C, centrifugation for 10 min) to obtain plasma.
  • the sample was divided into 1 portion, 250 ⁇ l/portion.
  • the separated plasma was stored in a -80°C environment.
  • the drug concentration in plasma was determined by HPLC-MS/MS.
  • the blood drug concentration of the long-acting preparations of preparations 19-22 is released steadily, and the C max of the long-acting preparations is lower than the C max of the tablets, and there is no rapid or unexplained increase in exposure, which proves the safety of the preparations; the long-acting group significantly prolongs the half-life, and T 1/2 is 69.5-176.9 times that of the tablets T 1/2 ; the blood drug concentration during the entire administration period is between C min and C max of the dienogest tablets, and the blood drug concentration of the group with ester-terminated lactide-co-glycolide copolymer (7525) (preparation 21/22 group) has an upward trend compared with the group without addition (preparation 20) from 56 to 84 days.
  • preparation 21 is the preferred three-month sustained-release prescription.
  • the laparotomy was performed 14 to 21 days after surgery, and the length and width of the endometrial cyst were measured with a vernier caliper.
  • the patients were grouped according to the endometrial cyst volume and body weight.
  • the medication was started three days after the laparotomy and postoperative care. The specific grouping information is shown in Table 21.
  • the dosing groups were divided according to the cyst volume and body weight before dosing.
  • Animal weighing The animals were weighed and recorded before administration and twice a week after administration.
  • DNG table was administered orally by gavage, and preparations 19, 20, and 22 were injected subcutaneously (due to the high viscosity of the preparations, the dosage was verified by weighing the syringe containing the medicine before and after administration to each animal).
  • Dosing frequency G3-G4 were given once a day; the rest of the groups received a single subcutaneous injection.
  • dosage (mL) animal body weight (kg) * dosage volume (mL/kg).
  • Animal weighing The animals were weighed and recorded before administration and twice a week after administration.
  • the animals were anesthetized on D0, D42, and D84, and the laparotomy was performed and the length and width of the endometrial cyst were measured with a vernier caliper.
  • the lactide-co-glycolide copolymer is dissolved in NMP solvent until the polymer solution is clear and transparent, and the solution is filled into a female syringe.
  • the syringe can be sterilized by filtration or terminal irradiation with gamma rays.
  • the dienogest powder is filled in a male syringe, which is a sterile lyophilized powder or irradiated sterilized after filling.
  • a male syringe which is a sterile lyophilized powder or irradiated sterilized after filling.
  • the product is reconstituted by connecting two syringes and mixing them by reciprocating the plunger. After mixing for multiple cycles, the powder is completely dissolved in the polymer solution. After sufficient mixing, the preparation is withdrawn into the female syringe, connected to a needle with a protective device, and the final subcutaneous injection is completed, and the injection volume is ⁇ 1mL.
  • the double-packed preparation can meet the content uniformity requirement by mixing more than 200 times before injection.
  • a single or double-packed dienogest long-acting delivery injectable composition is prepared, and the preparation has good physicochemical stability.
  • the pharmacokinetic experiments in rats and dogs show that the preparation has low burst release and good safety, and the blood drug concentration range is between C min -C max of the tablet, and at the same time the blood drug concentration can be maintained for about 84 days, proving that it can be released for at least three months in a long-term manner. Subsequent replacement of different carrier models and proportions can adjust different dosing cycles, thereby achieving a long-term release of six months.

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Abstract

Disclosed are an in-situ subcutaneous implantable female hormone modulation pharmaceutical composition, a preparation method therefor, and use thereof. The composition comprises dienogest, a biodegradable thermoplastic polymer, and a polar aprotic organic liquid, and is used for treating endometriosis. The composition is a sustained-release delivery system, can be injected into tissues and solidify subcutaneously into a solid or gel monolithic implant, and has the characteristic of long-acting release.

Description

一种原位皮下植入的女性激素调节组合物及其制备方法和应用A female hormone regulating composition for in situ subcutaneous implantation and its preparation method and application

本申请要求以下两项在先申请的优先权：于2023年12月13日向中国国家知识产权局提交的专利申请号为202311716992.3，发明名称为“一种原位皮下植入的女性激素调节药物组合物及其制备方法和应用”的在先申请；以及于2024年12月02日向中国国家知识产权局提交的专利申请号为202411754679.3，发明名称为“一种原位皮下植入的女性激素调节药物组合物及其制备方法和应用”的在先申请。所述在先申请的全文通过引用的方式结合于本申请中。This application claims the priority of the following two prior applications: a prior application with patent application number 202311716992.3 filed with the State Intellectual Property Office of China on December 13, 2023, and the invention name is “A female hormone regulating pharmaceutical composition implanted subcutaneously in situ, and its preparation method and application”; and a prior application with patent application number 202411754679.3 filed with the State Intellectual Property Office of China on December 2, 2024, and the invention name is “A female hormone regulating pharmaceutical composition implanted subcutaneously in situ, and its preparation method and application”. The full text of the prior application is incorporated into this application by reference.

技术领域Technical Field

本发明属于药物制剂领域，涉及一种原位皮下植入的女性激素调节药物组合物及其制备方法和应用。The invention belongs to the field of pharmaceutical preparations, and relates to an in situ subcutaneously implanted female hormone regulating pharmaceutical composition, a preparation method and an application thereof.

背景技术Background Art

女性的激素水平失调可导致一系列疾病，女性激素及其激动剂/拮抗剂是这些女性疾病的常用药物，适应症有乳腺癌、子宫内膜异位症、激素补充等。常见药物例如：Hormone imbalance in women can lead to a series of diseases. Female hormones and their agonists/antagonists are commonly used drugs for these female diseases. Indications include breast cancer, endometriosis, hormone replacement, etc. Common drugs include:

氟维司群(Fulvestrant)，适用于治疗经过抗雌激素治疗疾病仍趋恶化的绝经后妇女所患的雌激素受体阳性的转移性乳腺癌，目前上市的氟维司群注射液处方中含有的成分有乙醇、苯甲醇、苯甲酸苄酯、蓖麻油等成分，使用时有许多禁忌证及不良反应。例如，乙醇有刺激性，容易过敏，导致乙醇过敏患者不能使用；苯甲酸苄酯的使用可能产生全身过敏反应、中枢神经系统刺激反应和痉挛等；苯甲醇的注射液必须注明禁用于儿童肌肉注射，不良反应较多，蓖麻油成分复杂，容易产生过敏反应。因此需开发处方中能够去除上述不良反应成分，可提高用药安全性，具有明显的临床优势的制剂。Fulvestrant is suitable for the treatment of estrogen receptor-positive metastatic breast cancer in postmenopausal women whose disease worsens after anti-estrogen treatment. The ingredients in the Fulvestrant injection currently on the market include ethanol, benzyl alcohol, benzyl benzoate, castor oil, etc., and there are many contraindications and adverse reactions when using it. For example, ethanol is irritating and prone to allergies, so patients with ethanol allergies cannot use it; the use of benzyl benzoate may cause systemic allergic reactions, central nervous system stimulation reactions and spasms; benzyl alcohol injection must be marked as prohibited for intramuscular injection in children, and there are many adverse reactions. Castor oil has a complex composition and is prone to allergic reactions. Therefore, it is necessary to develop a formulation that can remove the above-mentioned adverse reaction ingredients in the prescription, improve the safety of medication, and have obvious clinical advantages.

雌二醇(Estradiol)，是一种雌性激素，可调节体内的许多生理过程；主要用于改善更年期症状(如潮热和外阴阴道变化)，以及预防更年期妇女的骨质疏松症，需要长期用药。Estradiol is a female hormone that regulates many physiological processes in the body. It is mainly used to improve menopausal symptoms (such as hot flashes and vulvovaginal changes) and prevent osteoporosis in menopausal women, and requires long-term medication.

地诺孕素(Dienogest)，是一种混合型孕激素，它具有19-去甲睾丸酮衍生物和孕酮衍生物的双重性质，缓解内异症痛经的同时可以缩小卵巢子宫内膜异位囊肿，并且随用药时间的延长，缩小异位囊肿的效果更显著，地诺孕素可用于口服避孕药、雌激素缺乏的激素替代疗法和子宫内膜异位症的治疗。目前上市的地诺孕素制剂为单方或复方片剂，给药周期为每天一次，使用时要求最好每天同一时间服用，因此可能因患者不愿意或未能按处方口服药物而产生依从性差的问题。而内异症属于激素依赖性疾病，为了有效控制疾病进展，预防复发，地诺孕素需要长期连续服用。Dienogest is a mixed progestin with the dual properties of 19-nortestosterone derivatives and progesterone derivatives. It can relieve endometriosis dysmenorrhea and shrink ovarian endometriosis cysts. The effect of shrinking ectopic cysts is more significant as the medication time is prolonged. Dienogest can be used for oral contraceptives, hormone replacement therapy for estrogen deficiency and the treatment of endometriosis. The currently marketed dienogest preparations are single or compound tablets with a dosing cycle of once a day. It is best to take it at the same time every day. Therefore, poor compliance may occur due to the patient's unwillingness or failure to take the oral medication as prescribed. Endometriosis is a hormone-dependent disease. In order to effectively control the progression of the disease and prevent recurrence, dienogest needs to be taken continuously for a long time.

可见，女性激素调节药物期待降低给药频次、稳定长效释放的剂型研发问世，以实现药物的稳定释放、提高药物的生物利用度和疗效、同时减少不良反应和药物的使用量，更好地提升用药的顺应性。It can be seen that female hormone regulating drugs are looking forward to the development of dosage forms that reduce the frequency of dosing and have stable long-acting release, so as to achieve stable release of drugs, improve drug bioavailability and efficacy, reduce adverse reactions and drug usage, and better improve medication compliance.

发明内容Summary of the invention

为了改善上述技术问题，本发明提供一种组合物，其包含：(a)可生物降解热塑性聚合物；(b)极性非质子性有机液体；(c)地诺孕素。In order to improve the above technical problems, the present invention provides a composition comprising: (a) a biodegradable thermoplastic polymer; (b) a polar aprotic organic liquid; and (c) dienogest.

根据本发明的实施方案，所述可生物降解热塑性聚合物可以合适的量存在，条件是所述可生物降解热塑性聚合物至少基本上不溶于水性介质或体液中。According to embodiments of the present invention, the biodegradable thermoplastic polymer may be present in a suitable amount, provided that the biodegradable thermoplastic polymer is at least substantially insoluble in aqueous media or body fluids.

根据本发明的实施方案，所述可生物降解热塑性聚合物选自聚乙交酯(PGA)、聚丙交酯(PLA)、聚己内酯(PCL)和丙交酯乙交酯共聚物(PLGA)中的一种或多种组合，优选为聚丙交酯和/或丙交酯乙交酯共聚物。According to an embodiment of the present invention, the biodegradable thermoplastic polymer is selected from one or more combinations of polyglycolide (PGA), polylactide (PLA), polycaprolactone (PCL) and poly(lactide-co-glycolide) (PLGA), preferably polylactide and/or poly(lactide-co-glycolide).

根据本发明的实施方案，当所述可生物降解热塑性聚合物选自上述两种聚合物时，二者的质量比为(1-7):1，例如(1.3-6):1，示例性为1.5:1、2:1、3:1、3.5:1、4:1、4.5:1、5:1或5.5:1。在一些实施方案中，所述可生物降解热塑性聚合物选自聚丙交酯和丙交酯乙交酯共聚物，二者的质量比为(1-7):1，例如(1.3-6):1，示例性为1.5:1、2:1、3:1、3.5:1、4:1、4.5:1、5:1或5.5:1。According to an embodiment of the present invention, when the biodegradable thermoplastic polymer is selected from the above two polymers, the mass ratio of the two is (1-7): 1, such as (1.3-6): 1, and exemplarily 1.5: 1, 2: 1, 3: 1, 3.5: 1, 4: 1, 4.5: 1, 5: 1 or 5.5: 1. In some embodiments, the biodegradable thermoplastic polymer is selected from polylactide and poly(lactide-co-glycolide), and the mass ratio of the two is (1-7): 1, such as (1.3-6): 1, and exemplarily 1.5: 1, 2: 1, 3: 1, 3.5: 1, 4: 1, 4.5: 1, 5: 1 or 5.5: 1.

在一些实施方案中，所述聚丙交酯为羧基或酯基封端。In some embodiments, the polylactide is carboxyl or ester terminated.

在一些实施方案中，所述丙交酯乙交酯共聚物为羧基或酯基封端。In some embodiments, the lactide-co-glycolide copolymer is carboxyl or ester terminated.

在一些实施方案中，所述丙交酯乙交酯共聚物中丙交酯和乙交酯的摩尔比为(50-85):(50-15)，例如为50:50、75:25、85:15等。In some embodiments, the molar ratio of lactide to glycolide in the lactide-glycolide copolymer is (50-85):(50-15), for example, 50:50, 75:25, 85:15, etc.

根据本发明的实施方案，以质量百分比计，所述可生物降解热塑性聚合物占所述组合物的10wt.％至95wt.％，优选20wt.％至70wt.％，还优选30wt.％至60wt.％。示例性地，所述可生物降解热塑性聚合物占所述组合物的15wt.％、25wt.％、35wt.％、36.6wt.％、38.1wt.％、40wt.％、41.1wt.％、42.5wt.％、42.8wt.％、43.75wt.％、45wt.％、50wt.％、55wt.％、65wt.％、75wt.％、80wt.％、85wt.％、90wt.％。According to an embodiment of the present invention, in terms of mass percentage, the biodegradable thermoplastic polymer accounts for 10 wt.% to 95 wt.%, preferably 20 wt.% to 70 wt.%, and also preferably 30 wt.% to 60 wt.%. Exemplarily, the biodegradable thermoplastic polymer accounts for 15 wt.%, 25 wt.%, 35 wt.%, 36.6 wt.%, 38.1 wt.%, 40 wt.%, 41.1 wt.%, 42.5 wt.%, 42.8 wt.%, 43.75 wt.%, 45 wt.%, 50 wt.%, 55 wt.%, 65 wt.%, 75 wt.%, 80 wt.%, 85 wt.%, 90 wt.% of the composition.

根据本发明的实施方案，所述可生物降解热塑性聚合物的平均分子量为10,000道尔顿(Da)至45,000道尔顿，优选为约15,000道尔顿至约30,000道尔顿。According to an embodiment of the present invention, the average molecular weight of the biodegradable thermoplastic polymer is from 10,000 Daltons (Da) to 45,000 Daltons, preferably from about 15,000 Daltons to about 30,000 Daltons.

根据本发明示例性的实施方案，所述可生物降解热塑性聚合物选自羧基封端的丙交酯乙交酯共聚物，丙交酯和乙交酯的摩尔比50:50、75:25或85:15。According to an exemplary embodiment of the present invention, the biodegradable thermoplastic polymer is selected from carboxyl-terminated lactide-glycolide copolymers, and the molar ratio of lactide to glycolide is 50:50, 75:25 or 85:15.

根据本发明示例性的实施方案，所述可生物降解热塑性聚合物选自酯基封端的丙交酯乙交酯共聚物，丙交酯和乙交酯的摩尔比50:50、75:25或85:15。According to an exemplary embodiment of the present invention, the biodegradable thermoplastic polymer is selected from ester-terminated lactide-glycolide copolymers, and the molar ratio of lactide to glycolide is 50:50, 75:25 or 85:15.

根据本发明示例性的实施方案，所述可生物降解热塑性聚合物选自羧基封端的聚丙交酯。According to an exemplary embodiment of the present invention, the biodegradable thermoplastic polymer is selected from carboxyl-terminated polylactide.

根据本发明示例性的实施方案，所述可生物降解热塑性聚合物选自羧基封端的聚丙交酯和酯基封端的丙交酯乙交酯共聚物。According to an exemplary embodiment of the present invention, the biodegradable thermoplastic polymer is selected from carboxyl-terminated polylactide and ester-terminated lactide-glycolide copolymer.

根据本发明的实施方案，所述极性非质子性有机液体选自生物相容性极性非质子性有机液体，例如选自N-甲基吡咯烷酮、2-吡咯烷酮、N,N-二甲基甲酰胺、二甲基亚砜、碳酸丙二醇酯、己内酰胺、三醋精或前述任意液体两种以上的组合物；优选为二甲基亚砜和/或N-甲基吡咯烷酮。According to an embodiment of the present invention, the polar aprotic organic liquid is selected from biocompatible polar aprotic organic liquids, for example, selected from N-methylpyrrolidone, 2-pyrrolidone, N,N-dimethylformamide, dimethyl sulfoxide, propylene carbonate, caprolactam, triacetin or a combination of two or more of any of the foregoing liquids; preferably dimethyl sulfoxide and/or N-methylpyrrolidone.

根据本发明的实施方案，以质量百分比计，所述极性非质子性有机液体占所述组合物的约10wt.％至约90wt.％，优选约30wt.％至约70wt.％。示例性地，所述极性非质子性有机液体占所述组合物的15wt.％、25wt.％、35wt.％、36.6wt.％、40wt.％、43.4wt.％、45wt.％、50wt.％、55wt.％、65wt.％、75wt.％、80wt.％、85wt.％。According to an embodiment of the present invention, the polar aprotic organic liquid accounts for about 10wt.% to about 90wt.% of the composition, preferably about 30wt.% to about 70wt.%. Exemplarily, the polar aprotic organic liquid accounts for 15wt.%, 25wt.%, 35wt.%, 36.6wt.%, 40wt.%, 43.4wt.%, 45wt.%, 50wt.%, 55wt.%, 65wt.%, 75wt.%, 80wt.%, 85wt.% of the composition.

根据本发明的实施方案，所述可生物降解热塑性聚合物与所述极性非质子性有机液体的质量比为0.5-2.0，例如0.5-1.5、0.5-1.1、0.5-1.0、0.5-0.9或0.6-0.88，示例性为0.7、0.75、0.8、0.84、0.85、1.0。According to an embodiment of the present invention, the mass ratio of the biodegradable thermoplastic polymer to the polar aprotic organic liquid is 0.5-2.0, such as 0.5-1.5, 0.5-1.1, 0.5-1.0, 0.5-0.9 or 0.6-0.88, exemplified by 0.7, 0.75, 0.8, 0.84, 0.85, 1.0.

根据本发明的实施方案，所述地诺孕素在所述组合物中的质量百分比不低于0.001wt.％，其上限为地诺孕素在所述组合物中分散性的限度。优选地，所述地诺孕素的质量百分比为约0.5wt.％至约50wt.％，更优选为约1wt.％至约30wt.％。示例性地，所述地诺孕素的质量百分比为0.1wt.％、1.5wt.％、2wt.％、3wt.％、4wt.％、5wt.％、6wt.％、7wt.％、8wt.％、9wt.％、10wt.％、11wt.％、12wt.％、13wt.％、14wt.％、15wt.％、16wt.％、17wt.％、18wt.％、19wt.％、20wt.％、25wt.％、35wt.％、40wt.％、45wt.％。According to an embodiment of the present invention, the mass percentage of the dienogest in the composition is not less than 0.001wt.%, and its upper limit is the limit of the dispersibility of the dienogest in the composition. Preferably, the mass percentage of the dienogest is about 0.5wt.% to about 50wt.%, more preferably about 1wt.% to about 30wt.%. Exemplarily, the mass percentage of the dienogest is 0.1wt.%, 1.5wt.%, 2wt.%, 3wt.%, 4wt.%, 5wt.%, 6wt.%, 7wt.%, 8wt.%, 9wt.%, 10wt.%, 11wt.%, 12wt.%, 13wt.%, 14wt.%, 15wt.%, 16wt.%, 17wt.%, 18wt.%, 19wt.%, 20wt.%, 25wt.%, 35wt.%, 40wt.%, 45wt.%.

根据本发明优选地实施方案，所述组合物包含聚丙交酯和/或丙交酯乙交酯共聚物30wt.％至60wt.％，N-甲基吡咯烷酮或二甲基亚砜30wt.％至70wt.％，地诺孕素1wt.％至30wt.％。According to a preferred embodiment of the present invention, the composition comprises 30 wt.% to 60 wt.% of polylactide and/or lactide-glycolide copolymer, 30 wt.% to 70 wt.% of N-methylpyrrolidone or dimethyl sulfoxide, and 1 wt.% to 30 wt.% of dienogest.

根据本发明示例性的实施方案，所述组合物选自下述任意配方的组合物：According to an exemplary embodiment of the present invention, the composition is selected from the following compositions of any formula:

配方一：羧基封端的丙交酯乙交酯共聚物(丙交酯与乙交酯的摩尔比50:50)43.75wt％、N-甲基吡咯烷酮50wt％、地诺孕素6.25wt％；Formula 1: 43.75wt% of carboxyl-terminated lactide-glycolide copolymer (molar ratio of lactide to glycolide 50:50), 50wt% of N-methylpyrrolidone, and 6.25wt% of dienogest;

配方二：酯基封端的丙交酯乙交酯共聚物(丙交酯与乙交酯的摩尔比50:50)43.75wt％、N-甲基吡咯烷酮50wt％、地诺孕素6.25wt％；Formula 2: 43.75wt% of ester-terminated lactide-glycolide copolymer (molar ratio of lactide to glycolide 50:50), 50wt% of N-methylpyrrolidone, and 6.25wt% of dienogest;

配方三：羧基封端的丙交酯乙交酯共聚物(丙交酯与乙交酯的摩尔比75:25)40wt％、N-甲基吡咯烷酮47.5wt％、地诺孕素12.5wt％；Formulation 3: 40 wt% of carboxyl-terminated lactide-glycolide copolymer (molar ratio of lactide to glycolide 75:25), 47.5 wt% of N-methylpyrrolidone, and 12.5 wt% of dienogest;

配方四：酯基封端的丙交酯乙交酯共聚物(丙交酯与乙交酯的摩尔比75:25)40wt％、N-甲基吡咯烷酮47.5wt％、地诺孕素12.5wt％；Formulation 4: 40 wt% of ester-terminated lactide-glycolide copolymer (molar ratio of lactide to glycolide 75:25), 47.5 wt% of N-methylpyrrolidone, and 12.5 wt% of dienogest;

配方五:羧基封端聚丙交酯38.1wt％、N-甲基吡咯烷酮45.2wt％、地诺孕素16.7wt％Formula 5: 38.1 wt% carboxyl-terminated polylactide, 45.2 wt% N-methylpyrrolidone, 16.7 wt% dienogest

配方六：酯基封端的丙交酯乙交酯共聚物(丙交酯与乙交酯的摩尔比50:50)41.1wt％、N-甲基吡咯烷酮48.9wt％、地诺孕素10.0wt％；Formulation 6: 41.1 wt% of ester-terminated lactide-glycolide copolymer (molar ratio of lactide to glycolide 50:50), 48.9 wt% of N-methylpyrrolidone, and 10.0 wt% of dienogest;

配方七：羧基封端的丙交酯乙交酯共聚物(丙交酯与乙交酯的摩尔比50:50)38.1wt％、N-甲基吡咯烷酮45.2wt％、地诺孕素16.7wt％；Formulation 7: 38.1 wt% of carboxyl-terminated lactide-glycolide copolymer (molar ratio of lactide to glycolide 50:50), 45.2 wt% of N-methylpyrrolidone, and 16.7 wt% of dienogest;

配方八：羧基封端的丙交酯乙交酯共聚物(丙交酯与乙交酯的摩尔比75:25)38.1wt％、N-甲基吡咯烷酮45.2wt％、地诺孕素16.7wt％；Formulation 8: 38.1 wt% of carboxyl-terminated lactide-glycolide copolymer (molar ratio of lactide to glycolide 75:25), 45.2 wt% of N-methylpyrrolidone, and 16.7 wt% of dienogest;

配方九：酯基封端的丙交酯乙交酯共聚物(丙交酯与乙交酯的摩尔比50:50)38.1wt％、N-甲基吡咯烷酮45.2wt％、地诺孕素16.7wt％；Formulation 9: 38.1 wt% of ester-terminated lactide-glycolide copolymer (molar ratio of lactide to glycolide 50:50), 45.2 wt% of N-methylpyrrolidone, and 16.7 wt% of dienogest;

配方十：酯基封端的丙交酯乙交酯共聚物(丙交酯与乙交酯的摩尔比50:50)41.1wt％、N-甲基吡咯烷酮48.9wt％、地诺孕素10.0wt％；Formulation 10: 41.1 wt% of ester-terminated lactide-glycolide copolymer (molar ratio of lactide to glycolide 50:50), 48.9 wt% of N-methylpyrrolidone, and 10.0 wt% of dienogest;

配方十一：酯基封端的丙交酯乙交酯共聚物(丙交酯与乙交酯的摩尔比50:50)42.8wt％、N-甲基吡咯烷酮50.9wt％、地诺孕素6.3wt％；Formulation 11: 42.8 wt % of ester-terminated lactide-glycolide copolymer (molar ratio of lactide to glycolide 50:50), 50.9 wt % of N-methylpyrrolidone, and 6.3 wt % of dienogest;

配方十二：酯基封端的丙交酯乙交酯共聚物(丙交酯与乙交酯的摩尔比50:50)16.7wt％、N-甲基吡咯烷酮66.6wt％、地诺孕素16.7wt％；Formulation 12: 16.7 wt % of ester-terminated lactide-glycolide copolymer (molar ratio of lactide to glycolide 50:50), 66.6 wt % of N-methylpyrrolidone, and 16.7 wt % of dienogest;

配方十三：羧基封端聚丙交酯36.6wt％、N-甲基吡咯烷酮43.4wt％、地诺孕素20.0wt％；Formulation 13: 36.6wt% of carboxyl-terminated polylactide, 43.4wt% of N-methylpyrrolidone, and 20.0wt% of dienogest;

配方十四：羧基封端聚丙交酯36.6wt％、二甲基亚砜43.4wt％、地诺孕素20.0wt％；Formulation 14: 36.6wt% of carboxyl-terminated polylactide, 43.4wt% of dimethyl sulfoxide, and 20.0wt% of dienogest;

配方十五：羧基封端聚丙交酯29.3wt％、酯基封端的丙交酯乙交酯共聚物(丙交酯与乙交酯的摩尔比75:25)7.3wt％、二甲基亚砜43.4wt％、地诺孕素20.0wt％；Formulation 15: 29.3 wt% of carboxyl-terminated polylactide, 7.3 wt% of ester-terminated lactide-glycolide copolymer (molar ratio of lactide to glycolide 75:25), 43.4 wt% of dimethyl sulfoxide, and 20.0 wt% of dienogest;

配方十六：羧基封端聚丙交酯22.0wt％、酯基封端的丙交酯乙交酯共聚物(丙交酯与乙交酯的摩尔比75:25)14.6wt％、二甲基亚砜43.4wt％、地诺孕素20.0wt％。Formulation 16: 22.0 wt% of carboxyl-terminated polylactide, 14.6 wt% of ester-terminated lactide-glycolide copolymer (molar ratio of lactide to glycolide 75:25), 43.4 wt% of dimethyl sulfoxide, and 20.0 wt% of dienogest.

根据本发明的实施方案，所述组合物的体积为约0.20mL至约2.0mL，优选为约0.20mL至约1.0mL，更优选为约0.20mL至约0.5mL。According to an embodiment of the present invention, the volume of the composition is about 0.20 mL to about 2.0 mL, preferably about 0.20 mL to about 1.0 mL, and more preferably about 0.20 mL to about 0.5 mL.

根据本发明的实施方案，所述组合物为可流动组合物，例如为凝胶。According to an embodiment of the present invention, the composition is a flowable composition, for example a gel.

根据本发明的实施方案，所述组合物为稳定缓释组合物，是适于在施用对象的体内形成原位固体、半固体或凝胶植入物的皮下注射持久无菌组合物。According to an embodiment of the present invention, the composition is a stable sustained-release composition, which is a subcutaneous injection durable sterile composition suitable for forming an in situ solid, semisolid or gel implant in the body of an administration subject.

根据本发明的实施方案，所述组合物的所述可生物降解热塑性聚合物、极性非质子性有机液体、地诺孕素混合放置，或所述可生物降解热塑性聚合物和极性非质子性有机液体的混合物与地诺孕素分别放置。According to an embodiment of the present invention, the biodegradable thermoplastic polymer, polar aprotic organic liquid, and dienogest of the composition are mixed and placed, or the mixture of the biodegradable thermoplastic polymer and polar aprotic organic liquid and dienogest are placed separately.

根据本发明的实施方案，所述组合物释放地诺孕素，地诺孕素可立即起效但无明显突释，例如所述组合物在植入给药后能提供稳定的血浆药物浓度，给药1-84天后提供片剂Cmin-Cmax的地诺孕素血浆浓度，且不需要额外补充口服制剂。According to an embodiment of the present invention, the composition releases dienogest, and dienogest can take effect immediately but without obvious burst release. For example, the composition can provide a stable plasma drug concentration after implantation and provide a plasma concentration of dienogest of C min -C max of the tablet after 1-84 days of administration, without the need for additional oral preparations.

根据本发明的实施方案，所述地诺孕素的释放时间可持续1-6个月，用于每次给予需要该组合物的患者50-300mg地诺孕素。According to an embodiment of the present invention, the release time of the dienogest can last for 1-6 months, and 50-300 mg of dienogest is administered to a patient in need of the composition each time.

根据本发明的实施方案，所述组合物具有良好的物理化学稳定性，例如在2-8℃可保存6-24个月，优选可保存12个月，更优选可保存24个月。According to an embodiment of the present invention, the composition has good physical and chemical stability, for example, it can be stored at 2-8° C. for 6-24 months, preferably for 12 months, and more preferably for 24 months.

本发明还提供上述组合物在制备治疗药物制剂或医疗器械中的应用。The present invention also provides the use of the above composition in preparing therapeutic drug preparations or medical devices.

根据本发明的实施方案，所述药物制剂、医疗器械用于治疗子宫内膜异位症。According to an embodiment of the present invention, the pharmaceutical preparation and medical device are used to treat endometriosis.

根据本发明的实施方案，所述药物制剂可以为注射剂。According to an embodiment of the present invention, the pharmaceutical preparation may be an injection.

根据本发明的实施方案，所述医疗器械为试剂盒。According to an embodiment of the present invention, the medical device is a kit.

本发明还提供一种试剂盒，包括所述的组合物。The invention also provides a kit, comprising the composition.

根据本发明的实施方案，所述试剂盒还包括容纳所述组合物的容器，例如包括第一容器和第二容器，或者包括一个单支容器例如预灌封注射器。According to an embodiment of the present invention, the kit further comprises a container for containing the composition, for example, a first container and a second container, or a single container such as a prefilled syringe.

根据本发明的实施方案，所述第一容器用于容纳所述地诺孕素；所述第二容器用于容纳可生物降解热塑性聚合物和极性非质子性有机液体，优选用于容纳N-甲基吡咯烷酮和丙交酯乙交酯共聚物、N-甲基吡咯烷酮和聚丙交酯、二甲基亚砜与聚丙交酯及丙交酯乙交酯共聚物的混合物。优选地，所述第一容器可与所述第二容器相连接。According to an embodiment of the present invention, the first container is used to contain the dienogest; the second container is used to contain a biodegradable thermoplastic polymer and a polar aprotic organic liquid, preferably a mixture of N-methylpyrrolidone and lactide-co-glycolide, N-methylpyrrolidone and polylactide, dimethyl sulfoxide and polylactide and lactide-co-glycolide. Preferably, the first container can be connected to the second container.

本发明还提供一种制备所述组合物的方法，包括在给药前将所述可生物降解热塑性聚合物和极性非质子性有机液体的混合物与地诺孕素混合，例如至多混合300次，优选混合250次，更优选混合200次。The present invention also provides a method for preparing the composition, comprising mixing the mixture of the biodegradable thermoplastic polymer and the polar aprotic organic liquid with dienogest before administration, for example mixing up to 300 times, preferably mixing 250 times, more preferably mixing 200 times.

本发明还提供一种制备所述组合物的方法，包括在给药前将可生物降解热塑性聚合物、极性非质子性有机液体和地诺孕素混合。The present invention also provides a method for preparing the composition, comprising mixing a biodegradable thermoplastic polymer, a polar aprotic organic liquid and dienogest before administration.

本发明还提供一种女性的激素水平失调导致的疾病的治疗方法，包括向需要的患者施用治疗有效量的上述组合物；The present invention also provides a method for treating diseases caused by hormone imbalance in women, comprising administering a therapeutically effective amount of the above composition to a patient in need;

在一些实施方案中，所述疾病为子宫内膜异位症。In some embodiments, the disease is endometriosis.

本申请组合物和制剂中的组分百分比wt.％、wt％和％均代表质量百分比。The component percentages wt.%, wt% and % in the compositions and preparations of the present application all represent mass percentages.

术语“多种”指两种以上，例如为两种、三种或更多种。The term "plurality" refers to more than two, for example, two, three or more.

术语“患者”是指包括哺乳动物在内的任何动物，优选小鼠、大鼠、其它啮齿类动物、兔、狗、猫、猪、牛、羊、马或灵长类动物，最优选人。The term "patient" refers to any animal including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses or primates, and most preferably humans.

术语“治疗有效量”是指研究人员、兽医、医师或其它临床医师正在组织、系统、动物、个体或人中寻找的引起生物学或医学反应的活性化合物或药物的量，它包括以下一项或多项：(1)预防疾病：例如在易感染疾病、紊乱或病症但尚未经历或出现疾病病理或症状的个体中预防疾病、紊乱或病症。(2)抑制疾病：例如在正经历或出现疾病、紊乱或病症的病理或症状的个体中抑制疾病、紊乱或病症(即阻止病理和/或症状的进一步发展)。(3)缓解疾病：例如在正经历或出现疾病、紊乱或病症的病理或病症的个体中缓解疾病、紊乱或疾病(即逆转病理和/或病症)。The term "therapeutically effective amount" refers to the amount of an active compound or drug that elicits the biological or medical response that a researcher, veterinarian, physician or other clinician is seeking in a tissue, system, animal, individual or human, and includes one or more of the following: (1) Preventing disease: e.g., preventing a disease, disorder or condition in an individual who is susceptible to the disease, disorder or condition but does not yet experience or develop the pathology or symptoms of the disease. (2) Inhibiting disease: e.g., inhibiting a disease, disorder or condition (i.e., preventing further development of the pathology and/or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder or condition. (3) Alleviating disease: e.g., alleviating a disease, disorder or condition (i.e., reversing the pathology and/or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder or condition.

有益效果Beneficial Effects

本发明提供的药物组合物能长效释放地诺孕素，其至少能够取得下述一个效果：(a)相对小体积的注射剂；(b)注射部位的良好组织耐受性；(c)具有最小突释的更好的释放动力学；(d)在较少注射频率下的延长的药物释放持续时间；(e)稳定性好；(f)制备工艺简单、无菌控制难度相对低，易于产业化。The pharmaceutical composition provided by the present invention can release dienogest in a long-term manner, and can achieve at least one of the following effects: (a) a relatively small volume of injection; (b) good tissue tolerance at the injection site; (c) better release kinetics with minimal burst release; (d) extended drug release duration at a lower injection frequency; (e) good stability; and (f) a simple preparation process, relatively low difficulty in aseptic control, and easy industrialization.

附图说明BRIEF DESCRIPTION OF THE DRAWINGS

图1为雌二醇组合物的药代动力学曲线图；FIG1 is a pharmacokinetic curve diagram of an estradiol composition;

图2为地诺孕素组合物的大鼠体内药代动力学曲线图。FIG. 2 is a pharmacokinetic curve of the dienogest composition in rats.

图3为地诺孕素组合物的比格犬体内药代动力学曲线图。FIG. 3 is a pharmacokinetic curve of the dienogest composition in beagle dogs.

图4为地诺孕素组合物的大鼠体内给药前后子宫内膜体积变化图。FIG. 4 is a graph showing changes in endometrial volume before and after administration of the dienogest composition to rats.

图5为地诺孕素组合物的大鼠体内给药前后子宫内膜重量变化图。FIG. 5 is a graph showing changes in endometrial weight before and after administration of the dienogest composition to rats.

图6为地诺孕素组合物的大鼠体内给药前后体重趋势变化图。FIG6 is a graph showing the body weight change trend of rats before and after administration of the dienogest composition.

具体实施方式DETAILED DESCRIPTION

下文将结合具体实施例对本发明的技术方案做更进一步的详细说明。应当理解，下列实施例仅为示例性地说明和解释本发明，而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。The technical scheme of the present invention will be further described in detail below in conjunction with specific embodiments. It should be understood that the following embodiments are only exemplary descriptions and explanations of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are included in the scope that the present invention is intended to protect.

除非另有说明，以下实施例中使用的原料和试剂均为市售商品，或者可以通过已知方法制备。Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

表A
Table A

以丙交酯乙交酯共聚物(5050)为例，代表丙交酯和乙交酯的摩尔比为50：50的丙交酯乙交酯共聚物。Taking the lactide-glycolide copolymer (5050) as an example, it represents a lactide-glycolide copolymer in which the molar ratio of lactide to glycolide is 50:50.

实施例1氟维司群组合物制备Example 1 Preparation of Fulvestrant Composition

表1.氟维司群组合物处方
Table 1. Fulvestrant composition prescription

将丙交酯乙交酯共聚物溶解于极性非质子性有机液体中，直至聚合物溶液澄清透明，并向上述聚合物溶液中加入处方量的氟维司群，混合至活性成分分布均匀。The lactide-co-glycolide copolymer is dissolved in a polar aprotic organic liquid until the polymer solution is clear and transparent, and the prescribed amount of fulvestrant is added to the polymer solution and mixed until the active ingredient is evenly distributed.

本实施例目的制备氟维司群长效组合物，考察不同PLGA型号、端基及溶剂对制剂的影响。但发现氟维司群加入后溶液迅速分层，制剂呈两相存在，无法制备均一制剂。The purpose of this example is to prepare a long-acting composition of fulvestrant and investigate the effects of different PLGA models, end groups and solvents on the preparation. However, it was found that after adding fulvestrant, the solution was rapidly separated and the preparation existed in two phases, and a uniform preparation could not be prepared.

实施例2雌二醇组合物制备Example 2 Preparation of estradiol composition

表2.雌二醇组合物处方

Table 2. Estradiol composition prescription

将丙交酯乙交酯共聚物溶解于NMP中，直至聚合物溶液澄清透明，并向上述聚合物溶液中加入处方量的雌二醇，混合至活性成分分布均匀。The lactide-co-glycolide copolymer was dissolved in NMP until the polymer solution was clear and transparent, and the prescribed amount of estradiol was added to the above polymer solution and mixed until the active ingredients were evenly distributed.

效果例1雌二醇长效组合物大鼠药代动力学试验Effect Example 1 Pharmacokinetics of Estradiol Long-Acting Composition in Rats

供试品1：根据制剂5制备雌二醇凝胶，规格0.8mg/ml。Test sample 1: Estradiol gel was prepared according to Preparation 5, with a specification of 0.8 mg/ml.

供试品2：根据制剂6制备雌二醇凝胶，规格0.8mg/ml。Test sample 2: Estradiol gel was prepared according to Preparation 6, with a specification of 0.8 mg/ml.

对照品：市售雌二醇片(Abbott Healthcare Products B.V.)，规格1mg。Reference substance: Commercially available estradiol tablets (Abbott Healthcare Products B.V.), specification 1 mg.

试验动物：Sprague Dawley大鼠(SPF级)，雄性SD大鼠，年龄月6-8周，体重200-220g，每组6只，原始来源：斯贝福(北京)生物技术有限公司；合格证号：110324220107108468；生产许可证号：SCXK(京)2019-0010。Experimental animals: Sprague Dawley rats (SPF grade), male SD rats, aged 6-8 weeks, weighing 200-220 g, 6 rats in each group, original source ... male SD rats, male SD rats, male SD rats, male SD rats, male SD rats, male SD rats, male SD rats, male SD rats, male SD rats, male SD rats, male SD rats, male SD rats, male SD rats, male SD rats, male

试验步骤：Test steps:

(1)分组及试验设计具体见下表3。(1) Grouping and experimental design are detailed in Table 3.

表3.雌二醇药代动力学给药方案
Table 3. Estradiol pharmacokinetics dosing regimen

备注：对照品口服生物利用度5％计Note: The oral bioavailability of the reference substance is 5%

(2)采集样本(2) Sample collection

第1组：皮下注射，0h(给药前)和给药后0.5h、1h、2h、4h、6h、8h、1d、7d、14d、30d、45d、60d采集血样，测雌二醇血药浓度。Group 1: Subcutaneous injection, blood samples were collected at 0h (before administration) and 0.5h, 1h, 2h, 4h, 6h, 8h, 1d, 7d, 14d, 30d, 45d, and 60d after administration to measure the blood concentration of estradiol.

第2组：皮下注射，0h(给药前)和给药后、0.5h、1h、2h、4h、6h、8h、1d、7d、14d、30d、36d采集血样，测雌二醇血药浓度。Group 2: Subcutaneous injection, blood samples were collected at 0h (before administration) and 0.5h, 1h, 2h, 4h, 6h, 8h, 1d, 7d, 14d, 30d, and 36d after administration to measure the blood concentration of estradiol.

第3组：灌胃，0h(给药前)和给药后0.5h、1h、2h、4h、6h、8h、24h采集血样，测雌二醇血药浓度。将收集的血液样本置于肝素抗凝型采血管中，离心分离血浆(离心力4000rpm，离心10min，2-8℃)。血浆样本在送样前存放于-40℃冰箱内。以HPLC-MS/MS测定血浆中的药物浓度。Group 3: Gavage, blood samples were collected at 0h (before administration) and 0.5h, 1h, 2h, 4h, 6h, 8h, and 24h after administration to measure the blood concentration of estradiol. The collected blood samples were placed in heparin anticoagulation blood collection tubes and centrifuged to separate plasma (centrifugal force 4000rpm, centrifugation 10min, 2-8℃). The plasma samples were stored in a -40℃ refrigerator before delivery. The drug concentration in plasma was determined by HPLC-MS/MS.

表4.大鼠血浆中的雌二醇PK参数

Table 4. Estradiol PK parameters in rat plasma

表5.雌二醇血药浓度
Table 5. Estradiol blood concentration

由表4-5和图1可知，雌二醇长效组合物突释明显，供试品1和供试品2的Cmax为83.30ng/ml和100.36ng/ml，对照品片剂Cmax为0.11ng/ml，凝胶突释为片剂的757-912倍，剂量倾卸可能带来安全性问题。因而对于长效制剂，必须高度重视安全性问题。As shown in Tables 4-5 and Figure 1, the burst release of the long-acting composition of estradiol is obvious, the Cmax of test sample 1 and test sample 2 is 83.30 ng/ml and 100.36 ng/ml, the Cmax of the control tablet is 0.11 ng/ml, and the burst release of the gel is 757-912 times that of the tablet. Dose dumping may bring safety problems. Therefore, for long-acting preparations, safety issues must be highly valued.

实施例3地诺孕素组合物制备Example 3 Preparation of Dienogest Composition

将丙交酯乙交酯共聚物溶解于NMP中，直至聚合物溶液澄清透明，并向上述聚合物溶液中加入处方量的地诺孕素，混合至活性成分分布均匀。将上述产品灌装于预灌封注射器中，使用时拧下护帽连接带有保护装置的针头，供直接完成皮下注射给药。Dissolve the lactide-co-glycolide copolymer in NMP until the polymer solution is clear and transparent, and add the prescribed amount of dienogest to the polymer solution and mix until the active ingredients are evenly distributed. Fill the above product into a prefilled syringe, unscrew the protective cap when using it, and connect the needle with a protective device for direct subcutaneous injection.

表6.地诺孕素组合物制备处方

Table 6. Dienogest composition preparation formula

表6制备得到的地诺孕素组合物均为均一透明或白色至乳白色制剂。The dienogest compositions prepared in Table 6 are all uniform transparent or white to milky white preparations.

实施例4可注射组合物稳定性研究Example 4 Stability study of injectable composition

为考察地诺孕素可注射组合物的稳定性，将表7制备好的制剂灌装于预灌封注射器中，将样品2-8℃放置6个月，考察地诺孕素含量、有关物质、丙交酯乙交酯共聚物分子量的变化。In order to investigate the stability of the dienogest injectable composition, the preparations prepared in Table 7 were filled into prefilled syringes, and the samples were placed at 2-8°C for 6 months to investigate the changes in dienogest content, related substances, and molecular weight of the lactide-co-glycolide copolymer.

表7.地诺孕素组合物制备处方
Table 7. Dienogest composition preparation formula

表8.地诺孕素组合物稳定性数据
Table 8. Dienogest composition stability data

如表8所示，地诺孕素样品稳定性良好，2-8℃放置6个月，地诺孕素含量、有关物质、丙交酯乙交酯共聚物的分子量均无显著变化。As shown in Table 8, the dienogest sample has good stability. After being placed at 2-8°C for 6 months, there is no significant change in the dienogest content, related substances, and molecular weight of the lactide-co-glycolide copolymer.

实施例5可注射组合物释放研究结果Example 5 Results of release studies of injectable compositions

在大鼠中进行了表9所示的制剂13-18这6个制剂的0.5和24小时体内释放研究(给药方案如表10所示)，以确保控制制剂突释现象，考察制剂的安全性，同时筛选载药量、聚合物浓度、聚合物中丙交酯与乙交酯比例、聚合物封端的影响。结果参见表11和表12。The 0.5 and 24 hour in vivo release studies of the six formulations 13-18 shown in Table 9 were conducted in rats (dosing regimens are shown in Table 10) to ensure the control of the burst release phenomenon of the formulations, investigate the safety of the formulations, and screen the effects of drug loading, polymer concentration, ratio of lactide to glycolide in the polymer, and polymer end-capping. The results are shown in Tables 11 and 12.

表9.地诺孕素组合物处方
Table 9. Dienogest Composition Prescription

表10.地诺孕素组合物释放研究给药方案
Table 10. Dosing regimen for dienogest composition release studies

表11.来自地诺孕素组合物0.5h地诺孕素血浆水平


Table 11. 0.5h Dienogest Plasma Levels from Dienogest Compositions


表12.来自地诺孕素组合物24h地诺孕素释放

Table 12. 24h Dienogest Release from Dienogest Compositions

结论：in conclusion:

1.随着载药量的降低，0.5h平均血浆浓度呈增高趋势，且24小时平均释放值释放增多，说明载药量越低，突释越高。1. As the drug loading decreases, the average plasma concentration at 0.5h tends to increase, and the average release value at 24h increases, indicating that the lower the drug loading, the higher the burst release.

2.制剂14的0.5h平均血浆浓度和24小时平均释放值均低于制剂18，说明聚合物浓度越高，地诺孕素的突释越低。2. The 0.5h mean plasma concentration and 24h mean release value of preparation 14 were lower than those of preparation 18, indicating that the higher the polymer concentration, the lower the burst release of dienogest.

3.制剂13的0.5h平均血浆浓度和24小时平均释放值均高于制剂15，说明聚合物中丙交酯的比例越高，突释越低。3. The 0.5h average plasma concentration and 24h average release value of formulation 13 were higher than those of formulation 15, indicating that the higher the proportion of lactide in the polymer, the lower the burst release.

4.处方比例相同的制剂，羧基端基和酯基端基之间0.5h的平均血浆浓度和24h药物释放的无显著差异，说明不同封端对释放基本无影响。4. For preparations with the same prescription ratio, there was no significant difference in the average plasma concentration at 0.5 h and the drug release at 24 h between the carboxyl end group and the ester end group, indicating that different end capping had little effect on the release.

总结：发现初始释放取决于聚合物浓度(浓度越高，地诺孕素的突释越低)、载药量(载药量较高，突释越低)和丙交酯与乙交酯的比例(丙交酯的比例越高，突释越低)，羧基端基和酯基端基之间的差异对释放基本无影响。载药量16.7％为优选处方。Summary: It was found that the initial release depends on the polymer concentration (the higher the concentration, the lower the burst release of dienogest), the drug loading (the higher the drug loading, the lower the burst release) and the ratio of lactide to glycolide (the higher the ratio of lactide, the lower the burst release), and the difference between the carboxyl end group and the ester end group has little effect on the release. The drug loading of 16.7% is the preferred formulation.

实施例6.地诺孕素长效组合物大鼠药代动力学试验Example 6. Pharmacokinetics of Dienogest Long-Acting Composition in Rats

(一)制备例(I) Preparation Example

表13.地诺孕素组合物处方

Table 13. Dienogest Composition Prescription

按照表13，称取处方量丙交酯乙交酯共聚物、NMP于离心除泡机小罐中，2200rpm混合5～10min，加入处方量地诺孕素，2200rpm混合10～20min，得到制剂13-15。According to Table 13, the prescribed amount of lactide-co-glycolide copolymer and NMP were weighed into a small tank of a centrifugal defoamer, mixed at 2200 rpm for 5-10 min, and the prescribed amount of dienogest was added, mixed at 2200 rpm for 10-20 min to obtain preparations 13-15.

(二)效果例(II) Effect examples

受试药：制剂13、14、15。Test drugs: Preparations 13, 14, and 15.

对照品：市售地诺孕素片：唯散宁，规格2mg(Jenapharm GmbH&Co.KG)。Reference substance: Commercially available dienogest tablets: Visanning, specification 2 mg (Jenapharm GmbH & Co. KG).

试验动物：Sprague Dawley大鼠(SPF级)，雌性SD大鼠，年龄月8-9周，体重200-220g，每组7只。Experimental animals: Sprague Dawley rats (SPF grade), female SD rats, aged 8-9 weeks, weighing 200-220 g, 7 rats in each group.

试验步骤：Test steps:

表14.分组及试验设计

备注：对照品口服生物利用度91％计Table 14. Grouping and experimental design

Note: The oral bioavailability of the reference product is 91%

采集样本Collecting samples

供试品组(即制剂13-15)：0h、0.5h、1h、2h、4h、6h、8h、1d、7d、14d、21d、28d、35d、42d采集血样，测地诺孕素血药浓度。For the test group (i.e., preparations 13-15): blood samples were collected at 0h, 0.5h, 1h, 2h, 4h, 6h, 8h, 1d, 7d, 14d, 21d, 28d, 35d, and 42d to measure the blood concentration of dienogest.

对照组：day1：0、0.5、1、1.5、2、4、6、8h；day2-4：0h，0.5h；day5：0、0.5、1、1.5、2、4、6、8、24h；采集血样，测地诺孕素血药浓度。Control group: day 1: 0, 0.5, 1, 1.5, 2, 4, 6, 8h; day 2-4: 0h, 0.5h; day 5: 0, 0.5, 1, 1.5, 2, 4, 6, 8, 24h; blood samples were collected to measure the blood concentration of dienogest.

备注：1小时及以内采血点采血时间窗±1分钟，其他时间点采血时间窗±5％。Note: The blood collection time window for blood collection points within 1 hour is ±1 minute, and the blood collection time window for other time points is ±5%.

血浆：按照取样各时间点经大鼠颈静脉采集全血0.4mL。EP管直立存放于2-8℃静置，离心处理(4000rpm，2～8℃，离心10min)后取血浆，分成2份，100μL+备份。分离出来的血浆保存于-40℃环境中。以HPLC-MS/MS测定血浆中的药物浓度。Plasma: 0.4 mL of whole blood was collected from the rat jugular vein at each sampling time point. The EP tube was stored upright at 2-8°C and centrifuged (4000 rpm, 2-8°C, centrifuged for 10 min) to obtain plasma, which was divided into 2 portions, 100 μL + backup. The separated plasma was stored at -40°C. The drug concentration in plasma was determined by HPLC-MS/MS.

表15.地诺孕素药代数据

注：/代表该点未进行取血Table 15. Pharmacokinetic data of dienogest

Note: / indicates that blood was not drawn at this point

表16.大鼠血浆中的地诺孕素PK参数
Table 16. Dienogest PK parameters in rat plasma

表16显示，对照组连续给药5天地诺孕素片，片剂的Cmin-Cmax的范围为0.35-385.14ng/ml，数据显示，三组被测试的地诺孕素可注射组合物(即制剂13-15)初始突释Cmax在118.54～136.04ng/ml，均低于片剂Cmax，说明地诺孕素组合物制剂的安全性良好。Table 16 shows that the control group was continuously administered with dienogest tablets for 5 days, and the C min -C max of the tablets ranged from 0.35 to 385.14 ng/ml. The data showed that the initial burst release C max of the three groups of dienogest injectable compositions tested (i.e., preparations 13-15) was 118.54 to 136.04 ng/ml, all lower than the C max of the tablets, indicating that the dienogest composition preparation has good safety.

表15和图2显示，制剂13-15受试组，在35天时，所有受试大鼠体内均存在可定量浓度的地诺孕素，在整个给药周期42天内，地诺孕素可注射组合物的血浆浓度在片剂的Cmin-Cmax之间，可满足一个月的长期释放。其中，发现共聚物的羧基封端和酯基封端会影响制剂的生物利用度AUClast，制剂13与制剂14的AUClast对比，结果显示羧基封端的共聚物制剂AUClast显著高于酯基封端共聚物制剂，因此优选羧基封端的共聚物。丙交酯的摩尔比例影响制剂的释放周期(释放周期评价指标：T1/2)，从一个月的释放周期考虑，优选丙交酯乙交酯共聚物(5050)羧基封端。Table 15 and Figure 2 show that in the test group of preparations 13-15, at 35 days, all the test rats had quantifiable concentrations of dienogest in their bodies. During the entire administration cycle of 42 days, the plasma concentration of the dienogest injectable composition was between the C min -C max of the tablet, which can meet the long-term release of one month. Among them, it was found that the carboxyl end-capping and ester end-capping of the copolymer would affect the bioavailability AUC last of the preparation. The AUC last of preparations 13 and 14 was compared, and the results showed that the AUC last of the carboxyl end-capped copolymer preparation was significantly higher than that of the ester end-capped copolymer preparation, so the carboxyl end-capped copolymer is preferred. The molar ratio of lactide affects the release cycle of the preparation (release cycle evaluation index: T 1/2 ). Considering the release cycle of one month, the carboxyl end-capping of the lactide-glycolide copolymer (5050) is preferred.

实施例7.地诺孕素长效组合物比格犬药代动力学试验Example 7. Pharmacokinetic study of dienogest long-acting composition in beagle dogs

(一)制备例(I) Preparation Example

表17.地诺孕素组合物处方
Table 17. Dienogest Composition Prescription

按照表17，称取处方量聚丙交酯、丙交酯乙交酯共聚物(若有)，加入DMSO/NMP于离心除泡机小罐中，2200rpm混合5～10min，加入处方量地诺孕素，2200rpm混合10～20min，得到制剂19-22。According to Table 17, the prescribed amount of polylactide and lactide-co-glycolide copolymer (if any) was weighed, DMSO/NMP was added to the small tank of a centrifugal defoamer, mixed at 2200 rpm for 5 to 10 min, the prescribed amount of dienogest was added, and mixed at 2200 rpm for 10 to 20 min to obtain preparations 19-22.

(二)效果例(II) Effect examples

受试药：制剂19、20、21、22。Test drugs: Preparations 19, 20, 21, and 22.

对照品：市售地诺孕素片：唯散宁，规格2mg(Jenapharm GmbH&Co.KG)。Reference substance: Commercially available dienogest tablets: Visanning, specification 2 mg (Jenapharm GmbH & Co. KG).

试验动物：比格犬，雌性，年龄月8-11周，体重8-14kg，每组6只。Experimental animals: Beagle dogs, female, aged 8-11 weeks, weighing 8-14 kg, 6 dogs in each group.

试验步骤:Test steps:

表18.分组及试验设计


备注：对照品口服生物利用度91％计Table 18. Grouping and experimental design


Note: The oral bioavailability of the reference product is 91%

采集样本Collecting samples

供试品组(即制剂19-22)：0、0.5h、1h、2h、4h、6h、8h、1d、7d、14d、21d、28d、56d、84d采集血样，测地诺孕素血药浓度。For the test group (i.e., preparations 19-22): blood samples were collected at 0, 0.5h, 1h, 2h, 4h, 6h, 8h, 1d, 7d, 14d, 21d, 28d, 56d, and 84d to measure the blood concentration of dienogest.

对照组：day1：0、0.5、1、2、4、6、8h；day2：0h，0.5h；day3：0、0.25、0.5、1、1.5、2、4、6、8h、12h、24h；采集血样，测地诺孕素血药浓度。Control group: day 1: 0, 0.5, 1, 2, 4, 6, 8h; day 2: 0h, 0.5h; day 3: 0, 0.25, 0.5, 1, 1.5, 2, 4, 6, 8h, 12h, 24h; blood samples were collected to measure the blood concentration of dienogest.

备注：1小时及以内采血点采血时间窗±1分钟，其他时间点采血时间窗±5％。Note: The blood collection time window for blood collection points within 1 hour is ±1 minute, and the blood collection time window for other time points is ±5%.

血浆：按照取样各时间点经犬头静脉采集全血1mL。EP管直立存放于2-8℃静置，离心处理(4000rpm，2～8℃，离心10min)后取血浆，样本分成1份，250μl/份。分离出来的血浆保存于-80℃环境中。以HPLC-MS/MS测定血浆中的药物浓度。Plasma: 1 mL of whole blood was collected from the dog's head vein at each sampling time point. The EP tube was stored upright at 2-8°C and centrifuged (4000 rpm, 2-8°C, centrifugation for 10 min) to obtain plasma. The sample was divided into 1 portion, 250 μl/portion. The separated plasma was stored in a -80°C environment. The drug concentration in plasma was determined by HPLC-MS/MS.

测试结果如图3、表19和表20所示。The test results are shown in Figure 3, Table 19 and Table 20.

表19.地诺孕素血药浓度

注：/代表该点未进行取血Table 19. Dienogest blood concentration

Note: / indicates that blood was not drawn at this point

表20.比格犬血浆中的地诺孕素PK参数
Table 20. Dienogest PK parameters in beagle dog plasma

制剂19-22长效制剂血药浓度平稳释放，长效制剂Cmax低于片剂Cmax，且无快速或无法解释的暴露增加，证明制剂的安全性；长效组显著延长半衰期，T1/2为片剂T1/2的69.5-176.9倍；整个给药期间血药浓度在地诺孕素片剂Cmin～Cmax之间，增加丙交酯乙交酯共聚物(7525)酯基封端的组(制剂21/22组)血药浓度在56-84天与未添加组相比(制剂20)有上升趋势，截止84天，各组长效制剂组的AUC是口服组的74.2％～101.1％，基本等效。综合考虑AUC、T1/2及药物在三个月的释放情况，制剂21为优选缓释三个月处方。The blood drug concentration of the long-acting preparations of preparations 19-22 is released steadily, and the C max of the long-acting preparations is lower than the C max of the tablets, and there is no rapid or unexplained increase in exposure, which proves the safety of the preparations; the long-acting group significantly prolongs the half-life, and T 1/2 is 69.5-176.9 times that of the tablets T 1/2 ; the blood drug concentration during the entire administration period is between C min and C max of the dienogest tablets, and the blood drug concentration of the group with ester-terminated lactide-co-glycolide copolymer (7525) (preparation 21/22 group) has an upward trend compared with the group without addition (preparation 20) from 56 to 84 days. As of 84 days, the AUC of each long-acting preparation group is 74.2% to 101.1% of the oral group, which is basically equivalent. Taking into account AUC, T 1/2 and the release of the drug in three months, preparation 21 is the preferred three-month sustained-release prescription.

实施例8.地诺孕素长效组合物大鼠药效学试验Example 8. Pharmacodynamics test of dienogest long-acting composition in rats

评估地诺孕素长效制剂19、制剂20、制剂22皮下注射后在子宫内膜异位症模型大鼠体内的药效指标评价。To evaluate the efficacy of long-acting dienogest preparations 19, 20, and 22 in endometriosis model rats after subcutaneous injection.

实验设计如下：The experimental design is as follows:

正常雌性大鼠按以下计划实施子宫内膜异位症或假手术，具体操作：舒泰-50麻醉后开腹，切除并游离结扎段的右侧子宫，分离子宫内膜与肌层，剪取两块约5mm×5mm内膜组织，将内膜的上皮层反向对着左侧腹腔壁，缝合或粘合固定；假手术：麻醉后开腹，切除并游离结扎段的右侧子宫后缝合。Normal female rats were subjected to endometriosis or sham surgery according to the following plan: laparotomy after anesthesia with Zota-50, the right uterus of the ligated segment was removed and freed, the endometrium and myometrium were separated, two pieces of endometrial tissue of about 5 mm × 5 mm were cut, the epithelial layer of the endometrium was reversed to face the left abdominal wall, and sutured or glued; sham surgery: laparotomy after anesthesia, the right uterus of the ligated segment was removed and freed, and then sutured.

术后14～21天开腹，用游标卡尺测量内膜囊肿的长度和宽度，根据公式V＝L*W2*0.5计算体积，根据内膜囊肿体积和体重分组，开腹后术后护理三天后开始给药，具体分组信息如表21。The laparotomy was performed 14 to 21 days after surgery, and the length and width of the endometrial cyst were measured with a vernier caliper. The volume was calculated according to the formula V=L*W2*0.5. The patients were grouped according to the endometrial cyst volume and body weight. The medication was started three days after the laparotomy and postoperative care. The specific grouping information is shown in Table 21.

表21.动物分组信息表

Table 21. Animal grouping information

给药：Dosage:

动物数量：每组6只动物给药组根据给药前囊肿体积及体重分组。Number of animals: 6 animals in each group. The dosing groups were divided according to the cyst volume and body weight before dosing.

动物称重：动物给药前称重并记录。给药后每周两次称重并记录。Animal weighing: The animals were weighed and recorded before administration and twice a week after administration.

禁食要求：所有动物给药前自由摄食摄水。Fasting requirements: All animals were allowed to eat and drink freely before administration.

给药途径：DNG table口服灌胃给药，制剂19、20和22皮下注射(由于制剂粘稠度高，每只动物给药前后通过称量带药注射器的重量进行给药量的复核)。Administration route: DNG table was administered orally by gavage, and preparations 19, 20, and 22 were injected subcutaneously (due to the high viscosity of the preparations, the dosage was verified by weighing the syringe containing the medicine before and after administration to each animal).

给药频率：G3-G4每天给药一次；其余组单次皮下注射。Dosing frequency: G3-G4 were given once a day; the rest of the groups received a single subcutaneous injection.

给药量计算：给药量(mL)＝动物体重(kg)*给药体积(mL/kg)。Calculation of dosage: dosage (mL) = animal body weight (kg) * dosage volume (mL/kg).

评价指标：Evaluation indicators:

动物称重：动物给药前称重并记录，给药后每周两次称重并记录。Animal weighing: The animals were weighed and recorded before administration and twice a week after administration.

内膜囊肿体积测量：Endometrial cyst volume measurement:

D0、D42、D84麻醉动物，开腹用游标卡尺测量内膜囊肿的长度和宽度，根据公式V＝L*W2*0.5计算囊肿体积。The animals were anesthetized on D0, D42, and D84, and the laparotomy was performed and the length and width of the endometrial cyst were measured with a vernier caliper. The cyst volume was calculated according to the formula V=L*W2*0.5.

内膜囊肿湿重:Endometrial cyst wet weight:

D84所有动物安乐死后，取内膜囊肿，称量重量。After all animals were euthanized on D84, the endometrial cysts were removed and weighed.

子宫大体情况拍照：Photo of the general condition of the uterus:

术前、术后D84动物麻醉开腹后，对子宫大体情况进行拍照(N＝10)。Before and after surgery, on D84, the animals were anesthetized and opened to examine the general condition of the uterus (N=10).

结果如下(参见图4、图5和图6)：G5-G7组间均可观察到子宫内膜不同程度退缩，结果没有显著性差异，均可维持3个月的药效。给药84天，各组动物体重无明显的影响。从内膜体积和重量趋势分析，制剂19和制剂20相当，制剂19结果相对更优，与片剂组药效相当。The results are as follows (see Figures 4, 5 and 6): Different degrees of endometrial retraction were observed in the G5-G7 groups, and there was no significant difference in the results. The efficacy of the drug was maintained for 3 months. After 84 days of administration, there was no significant effect on the body weight of the animals in each group. From the analysis of the endometrial volume and weight trend, preparation 19 and preparation 20 were equivalent, and the results of preparation 19 were relatively better, and the efficacy was equivalent to that of the tablet group.

实施例9.地诺孕素组合物双支装制剂制备Example 9. Preparation of double-pack preparation of dienogest composition

将丙交酯乙交酯共聚物溶解于NMP溶剂中，直至聚合物溶液澄清透明，并将该溶液填充到雌注射器内。该注射器可采用过滤除菌或γ射线进行终端辐照灭菌。The lactide-co-glycolide copolymer is dissolved in NMP solvent until the polymer solution is clear and transparent, and the solution is filled into a female syringe. The syringe can be sterilized by filtration or terminal irradiation with gamma rays.

将地诺孕素粉末填充在雄注射器中，该粉末为无菌冻干粉或填充之后进行辐照灭菌。在注射给药前，产品的重构是通过将两个注射器连接，通过柱塞往复推动的方式进行混合，混合多个循环后使粉末完全溶解于聚合物溶液中。在充分混合后，将制剂抽回雌注射器中连接带有保护装置的针头并完成最终皮下注射给药，注射给药体积＜1mL。The dienogest powder is filled in a male syringe, which is a sterile lyophilized powder or irradiated sterilized after filling. Before injection, the product is reconstituted by connecting two syringes and mixing them by reciprocating the plunger. After mixing for multiple cycles, the powder is completely dissolved in the polymer solution. After sufficient mixing, the preparation is withdrawn into the female syringe, connected to a needle with a protective device, and the final subcutaneous injection is completed, and the injection volume is <1mL.

表22.地诺孕素组合物处方
Table 22. Dienogest Composition Prescription

表23.组合物制剂混合次数考察
Table 23. Investigation of the number of times the composition preparation is mixed

结论：双支装制剂在注射给药前混合200次以上可满足含量均匀度。Conclusion: The double-packed preparation can meet the content uniformity requirement by mixing more than 200 times before injection.

可见，制备单支或双支装地诺孕素长效递送可注射组合物，该制剂物理化学稳定性良好，在大鼠及犬体内药动实验表明，该制剂突释低安全性好，血药浓度范围在片剂的Cmin-Cmax之间，且同时血药浓度能够维持84天左右，证明至少可以长效释放三个月，后续更换不同载体型号及比例可调节不同给药周期，从而达到长效释放六个月。It can be seen that a single or double-packed dienogest long-acting delivery injectable composition is prepared, and the preparation has good physicochemical stability. The pharmacokinetic experiments in rats and dogs show that the preparation has low burst release and good safety, and the blood drug concentration range is between C min -C max of the tablet, and at the same time the blood drug concentration can be maintained for about 84 days, proving that it can be released for at least three months in a long-term manner. Subsequent replacement of different carrier models and proportions can adjust different dosing cycles, thereby achieving a long-term release of six months.

以上，对本发明的实施方式进行了说明。但是，本发明不限定于上述实施方式。凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。The above is an explanation of the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims (12)

一种组合物，其特征在于，所述组合物包含：(a)可生物降解热塑性聚合物；(b)极性非质子性有机液体；(c)地诺孕素。A composition, characterized in that the composition comprises: (a) a biodegradable thermoplastic polymer; (b) a polar aprotic organic liquid; and (c) dienogest. 根据权利要求1所述的组合物，其特征在于，所述可生物降解热塑性聚合物选自聚乙交酯(PGA)、聚丙交酯(PLA)、聚己内酯(PCL)和丙交酯乙交酯共聚物(PLGA)中的一种或多种组合；The composition according to claim 1, characterized in that the biodegradable thermoplastic polymer is selected from one or more combinations of polyglycolide (PGA), polylactide (PLA), polycaprolactone (PCL) and poly(lactide-co-glycolide) (PLGA); 优选地，当所述可生物降解热塑性聚合物选自上述两种聚合物时，二者的质量比为(1-7):1。Preferably, when the biodegradable thermoplastic polymer is selected from the above two polymers, the mass ratio of the two is (1-7):1. 根据权利要求1或2所述的组合物，其特征在于，所述聚丙交酯或丙交酯乙交酯共聚物为羧基或酯基封端；The composition according to claim 1 or 2, characterized in that the polylactide or lactide-co-glycolide copolymer is carboxyl or ester terminated; 和/或，所述丙交酯乙交酯共聚物中丙交酯和乙交酯的摩尔比为(50-85):(50-15)；And/or, the molar ratio of lactide to glycolide in the lactide-glycolide copolymer is (50-85):(50-15); 和/或，以质量百分比计，所述可生物降解热塑性聚合物占所述组合物的10wt.％至95wt.％，优选20wt.％至70wt.％，还优选30wt.％至60wt.％；and/or, in terms of mass percentage, the biodegradable thermoplastic polymer accounts for 10 wt.% to 95 wt.%, preferably 20 wt.% to 70 wt.%, and further preferably 30 wt.% to 60 wt.% of the composition; 和/或，所述可生物降解热塑性聚合物的平均分子量为10,000道尔顿至45,000道尔顿。And/or, the biodegradable thermoplastic polymer has an average molecular weight of 10,000 Daltons to 45,000 Daltons. 根据权利要求1-3任一项所述的组合物，其特征在于，所述可生物降解热塑性聚合物选自羧基封端的丙交酯乙交酯共聚物，丙交酯和乙交酯的摩尔比50:50或75:25或85:15；The composition according to any one of claims 1 to 3, characterized in that the biodegradable thermoplastic polymer is selected from carboxyl-terminated lactide-glycolide copolymers, and the molar ratio of lactide to glycolide is 50:50 or 75:25 or 85:15; 或者，所述可生物降解热塑性聚合物选自酯基封端的丙交酯乙交酯共聚物，丙交酯和乙交酯的摩尔比50:50或75:25或85:15。Alternatively, the biodegradable thermoplastic polymer is selected from ester-terminated lactide-glycolide copolymers, and the molar ratio of lactide to glycolide is 50:50, 75:25 or 85:15. 根据权利要求1-4任一项所述的组合物，其特征在于，所述极性非质子性有机液体选自生物相容性极性非质子性有机液体，例如选自N-甲基吡咯烷酮、2-吡咯烷酮、N,N-二甲基甲酰胺、二甲基亚砜、碳酸丙二醇酯、己内酰胺、三醋精或前述任意液体两种以上的组合物；The composition according to any one of claims 1 to 4, characterized in that the polar aprotic organic liquid is selected from biocompatible polar aprotic organic liquids, for example, selected from N-methylpyrrolidone, 2-pyrrolidone, N,N-dimethylformamide, dimethyl sulfoxide, propylene carbonate, caprolactam, triacetin or a combination of two or more of any of the foregoing liquids; 和/或，以质量百分比计，所述极性非质子性有机液体占所述组合物的约10wt.％至约90wt.％，优选约30wt.％至约70wt.％。And/or, in terms of mass percentage, the polar aprotic organic liquid accounts for about 10 wt.% to about 90 wt.%, preferably about 30 wt.% to about 70 wt.% of the composition. 根据权利要求1-5任一项所述的组合物，其特征在于，所述可生物降解热塑性聚合物与所述极性非质子性有机液体的质量比为0.5-2.0，例如0.5-1.5、0.5-1.1、0.5-1.0、0.5-0.9或0.6-0.88；The composition according to any one of claims 1 to 5, characterized in that the mass ratio of the biodegradable thermoplastic polymer to the polar aprotic organic liquid is 0.5-2.0, such as 0.5-1.5, 0.5-1.1, 0.5-1.0, 0.5-0.9 or 0.6-0.88; 和/或，所述地诺孕素在所述组合物中的质量百分比不低于0.001wt.％，其上限为地诺孕素在所述组合物中分散性的限度；and/or, the mass percentage of dienogest in the composition is not less than 0.001wt.%, and the upper limit thereof is the dispersibility limit of dienogest in the composition; 优选地，所述组合物包含聚丙交酯和/或丙交酯乙交酯共聚物30wt.％至60wt.％，N-甲基吡咯烷酮或二甲基亚砜30wt.％至70wt.％，地诺孕素1wt.％至30wt.％。Preferably, the composition comprises 30 wt.% to 60 wt.% of polylactide and/or lactide-glycolide copolymer, 30 wt.% to 70 wt.% of N-methylpyrrolidone or dimethyl sulfoxide, and 1 wt.% to 30 wt.% of dienogest. 根据权利要求1-6任一项所述的组合物，其特征在于，所述组合物的体积为约0.20mL至约2.0mL；The composition according to any one of claims 1 to 6, characterized in that the volume of the composition is about 0.20 mL to about 2.0 mL; 和/或，所述组合物为可流动组合物，例如为凝胶；and/or, the composition is a flowable composition, such as a gel; 和/或，所述组合物为稳定缓释组合物，是适于在施用对象的体内形成原位固体、半固体或凝胶植入物的皮下注射持久无菌组合物；and/or, the composition is a stable sustained-release composition, which is a subcutaneous, durable, sterile composition suitable for forming an in situ solid, semisolid or gel implant in the body of a subject; 和/或，所述组合物的所述可生物降解热塑性聚合物、极性非质子性有机液体、地诺孕素混合放置，或所述可生物降解热塑性聚合物和极性非质子性有机液体的混合物与地诺孕素分别放置。And/or, the biodegradable thermoplastic polymer, polar aprotic organic liquid and dienogest of the composition are mixed and placed, or the mixture of the biodegradable thermoplastic polymer and polar aprotic organic liquid and dienogest are placed separately. 权利要求1-7任一项所述组合物在制备治疗药物制剂或医疗器械中的应用；Use of the composition according to any one of claims 1 to 7 in the preparation of therapeutic drug preparations or medical devices; 优选地，所述药物制剂、医疗器械用于治疗子宫内膜异位症；Preferably, the pharmaceutical preparation and medical device are used to treat endometriosis; 优选地，所述药物制剂为注射剂，所述医疗器械为试剂盒。Preferably, the pharmaceutical preparation is an injection, and the medical device is a kit. 一种试剂盒，其特征在于，所述试剂盒包括权利要求1-7任一项所述的组合物。A kit, characterized in that the kit comprises the composition according to any one of claims 1 to 7. 一种制备权利要求1-7任一项所述组合物的方法，其特征在于，所述方法在给药前将可生物降解热塑性聚合物、极性非质子性有机液体和地诺孕素混合；A method for preparing the composition according to any one of claims 1 to 7, characterized in that the method comprises mixing a biodegradable thermoplastic polymer, a polar aprotic organic liquid and dienogest before administration; 或者，所述方法包括在给药前将所述可生物降解热塑性聚合物和极性非质子性有机液体的混合物与地诺孕素混合。Alternatively, the method comprises mixing the mixture of the biodegradable thermoplastic polymer and the polar aprotic organic liquid with dienogest prior to administration. 一种女性的激素水平失调导致的疾病的治疗方法，其特征在于，所述治疗方法包括向需要的患者施用治疗有效量的权利要求1-7任一项所述组合物。A method for treating diseases caused by hormone imbalance in women, characterized in that the method comprises administering a therapeutically effective amount of the composition according to any one of claims 1 to 7 to a patient in need. 根据权利要求11所述的治疗方法，其特征在于，所述疾病为子宫内膜异位症。The treatment method according to claim 11, characterized in that the disease is endometriosis.
PCT/CN2024/138415 2023-12-13 2024-12-11 In-situ subcutaneous implantable female hormone modulation composition, preparation method therefor, and use thereof Pending WO2025124422A1 (en)

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