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WO2025124422A1 - Composition de modulation d'hormone femelle implantable sous-cutanée in situ, son procédé de préparation et son utilisation - Google Patents

Composition de modulation d'hormone femelle implantable sous-cutanée in situ, son procédé de préparation et son utilisation 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
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PCT/CN2024/138415
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English (en)
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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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

L'invention divulgue une composition pharmaceutique de modulation d'hormone femelle implantable sous-cutanée in situ, son procédé de préparation et son utilisation. La composition comprend du diénogest, un polymère thermoplastique biodégradable et un liquide organique aprotique polaire et est utilisée pour traiter l'endométriose. La composition est un système d'administration à libération prolongée, peut être injectée dans des tissus et se solidifier par voie sous-cutanée en un implant monolithique solide ou en gel, et présente la caractéristique d'une libération à action prolongée.
PCT/CN2024/138415 2023-12-13 2024-12-11 Composition de modulation d'hormone femelle implantable sous-cutanée in situ, son procédé de préparation et son utilisation Pending WO2025124422A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4938763A (en) * 1988-10-03 1990-07-03 Dunn Richard L Biodegradable in-situ forming implants and methods of producing the same
CN1474685A (zh) * 2000-09-21 2004-02-11 ������ʵ���ҹ�˾ 更高效的利普安聚合物释放制剂
CN101583364A (zh) * 2007-03-01 2009-11-18 拜耳先灵医药股份有限公司 减轻子宫内膜异位的药物制剂
CN101801415A (zh) * 2007-05-25 2010-08-11 托尔马医疗有限公司 利培酮化合物的持续递送制剂
CN107072948A (zh) * 2014-09-30 2017-08-18 田纳西大学研究基金会 用于长效药物传递的原位凝胶剂

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4938763A (en) * 1988-10-03 1990-07-03 Dunn Richard L Biodegradable in-situ forming implants and methods of producing the same
US4938763B1 (en) * 1988-10-03 1995-07-04 Atrix Lab Inc Biodegradable in-situ forming implants and method of producing the same
CN1474685A (zh) * 2000-09-21 2004-02-11 ������ʵ���ҹ�˾ 更高效的利普安聚合物释放制剂
CN101583364A (zh) * 2007-03-01 2009-11-18 拜耳先灵医药股份有限公司 减轻子宫内膜异位的药物制剂
CN101801415A (zh) * 2007-05-25 2010-08-11 托尔马医疗有限公司 利培酮化合物的持续递送制剂
CN107072948A (zh) * 2014-09-30 2017-08-18 田纳西大学研究基金会 用于长效药物传递的原位凝胶剂

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