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

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

A female hormone regulating composition for in situ subcutaneous implantation, and its preparation method and application

[0001] This application claims priority to the following two prior applications: Patent application No. 202311716992.3, filed with the State Intellectual Property Office of China on December 13, 2023, entitled “A female hormone-regulating pharmaceutical composition for in situ subcutaneous implantation, its preparation method, and use thereof”; and Patent application No. 202411754679.3, filed with the State Intellectual Property Office of China on December 2, 2024, entitled “A female hormone-regulating pharmaceutical composition for in situ subcutaneous implantation, its preparation method, and use thereof”. The entire contents of each of the prior applications are incorporated herein by reference. Technical Field

[0002] The present invention belongs to the field of pharmaceutical preparations, and relates to a female hormone regulating pharmaceutical composition for in situ subcutaneous implantation, a preparation method and an application thereof. Background Art

[0003] 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:

[0004] Fulvestrant is indicated for the treatment of estrogen receptor-positive metastatic breast cancer in postmenopausal women whose disease progresses despite anti-estrogen therapy. The currently marketed fulvestrant injection contains ingredients such as ethanol, benzyl alcohol, benzyl benzoate, and castor oil, which carry numerous contraindications and adverse reactions. For example, ethanol is an irritant and can easily cause allergic reactions, making it contraindicated in patients with ethanol allergies. Benzyl benzoate can cause systemic allergic reactions, central nervous system stimulation, and seizures. Benzyl alcohol injection must be clearly labeled as contraindicated for intramuscular injection in children, as it presents numerous adverse reactions. Castor oil, with its complex composition, can easily cause allergic reactions. Therefore, there is a need to develop a formulation that eliminates these adverse reaction ingredients, improves drug safety, and offers significant clinical advantages.

[0005] 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.

[0006] Dienogest is a mixed progestin with the dual properties of a 19-nortestosterone derivative and a progesterone derivative. It can relieve endometriosis-related dysmenorrhea while also shrinking ovarian endometriotic cysts. This reduction in size becomes more pronounced with prolonged use. Dienogest can be used in conjunction with oral contraceptives, hormone replacement therapy for estrogen deficiency, and the treatment of endometriosis. Currently available dienogest preparations are single or combined tablets, with a once-daily dosing cycle. Dosage is best taken at the same time each day, which can lead to poor compliance if patients are unwilling or unable to take the prescribed medication. Endometriosis is a hormone-dependent disease, and to effectively control disease progression and prevent recurrence, dienogest requires long-term, continuous administration.

[0007] It can be seen that female hormone-regulating drugs are looking forward to the development of dosage forms that reduce the frequency of administration and have stable long-term release, so as to achieve stable release of drugs, improve the bioavailability and efficacy of drugs, reduce adverse reactions and drug usage, and better improve medication compliance. Summary of the Invention

[0008] 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.

[0009] 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.

[0010] 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).

[0011] 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, for example (1.3-6): 1, and exemplified by 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, for example (1.3-6): 1, and exemplified by 1.5: 1, 2: 1, 3: 1, 3.5: 1, 4: 1, 4.5: 1, 5: 1, or 5.5: 1.

[0012] In some embodiments, the polylactide is carboxyl or ester terminated.

[0013] In some embodiments, the lactide-co-glycolide copolymer is carboxyl- or ester-terminated.

[0014] 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.

[0015] According to an embodiment of the present invention, the biodegradable thermoplastic polymer accounts for 10 wt.% to 95 wt.% of the composition, preferably 20 wt.% to 70 wt.%, and further 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.%, or 90 wt.% of the composition.

[0016] 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.

[0017] 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.

[0018] 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.

[0019] According to an exemplary embodiment of the present invention, the biodegradable thermoplastic polymer is selected from carboxyl-terminated polylactide.

[0020] According to an exemplary embodiment of the present invention, the biodegradable thermoplastic polymer is selected from carboxyl-terminated polylactide and ester-terminated lactide-co-glycolide.

[0021] According to an embodiment of the present invention, the polar aprotic organic liquid is selected from biocompatible polar aprotic organic liquids, for example, 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.

[0022] According to an embodiment of the present invention, the polar aprotic organic liquid accounts for about 10 wt.% to about 90 wt.% of the composition, preferably about 30 wt.% to about 70 wt.%. Exemplarily, the polar aprotic organic liquid accounts for 15 wt.%, 25 wt.%, 35 wt.%, 36.6 wt.%, 40 wt.%, 43.4 wt.%, 45 wt.%, 50 wt.%, 55 wt.%, 65 wt.%, 75 wt.%, 80 wt.%, or 85 wt.% of the composition.

[0023] 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, and exemplified by 0.7, 0.75, 0.8, 0.84, 0.85, 1.0.

[0024] According to an embodiment of the present invention, the mass percentage of dienogest in the composition is not less than 0.001wt.%, and its upper limit is the limit of the dispersibility of dienogest in the composition. Preferably, the mass percentage of dienogest is about 0.5wt.% to about 50wt.%, more preferably about 1wt.% to about 30wt.%. Exemplarily, the mass percentage of 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.%.

[0025] 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.

[0026] According to an exemplary embodiment of the present invention, the composition is selected from the following compositions:

[0027] Formulation 1: 43.75 wt% carboxyl-terminated lactide-glycolide copolymer (molar ratio of lactide to glycolide 50:50), 50 wt% N-methylpyrrolidone, and 6.25 wt% dienogest;

[0028] Formulation 2: 43.75 wt% of ester-terminated lactide-glycolide copolymer (molar ratio of lactide to glycolide 50:50), 50 wt% of N-methylpyrrolidone, and 6.25 wt% of dienogest;

[0029] Formulation 3: carboxyl-terminated lactide-glycolide copolymer (molar ratio of lactide to glycolide 75:25) 40 wt%, N-methylpyrrolidone 47.5 wt%, and dienogest 12.5 wt%;

[0030] 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;

[0031] Formula 5: 38.1 wt% carboxyl-terminated polylactide, 45.2 wt% N-methylpyrrolidone, 16.7 wt% dienogest

[0032] 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;

[0033] 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;

[0034] 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;

[0035] 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;

[0036] 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;

[0037] 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;

[0038] 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;

[0039] Formulation 13: carboxyl-terminated polylactide 36.6 wt%, N-methylpyrrolidone 43.4 wt%, and dienogest 20.0 wt%;

[0040] Formulation 14: carboxyl-terminated polylactide 36.6 wt%, dimethyl sulfoxide 43.4 wt%, and dienogest 20.0 wt%;

[0041] 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;

[0042] Formulation 16: carboxyl-terminated polylactide 22.0 wt%, ester-terminated lactide-glycolide copolymer (molar ratio of lactide to glycolide 75:25) 14.6 wt%, dimethyl sulfoxide 43.4 wt%, and dienogest 20.0 wt%.

[0043] According to an embodiment of the present invention, the volume of the composition is from about 0.20 mL to about 2.0 mL, preferably from about 0.20 mL to about 1.0 mL, and more preferably from about 0.20 mL to about 0.5 mL.

[0044] According to an embodiment of the present invention, the composition is a flowable composition, for example a gel.

[0045] According to an embodiment of the present invention, the composition is a stable sustained-release composition, which is a long-lasting sterile composition for subcutaneous injection suitable for forming an in situ solid, semisolid or gel implant in the body of an administered subject.

[0046] 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.

[0047] According to an embodiment of the present invention, the composition releases dienogest, which can take effect immediately without obvious burst release. For example, the composition can provide a stable plasma drug concentration after implantation and provide tablet C after 1-84 days of administration. min -C max The plasma concentration of dienogest was maintained at 1.5-2.0 mg / dL and no additional oral preparation was required.

[0048] 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 can be administered to a patient in need of the composition each time.

[0049] 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.

[0050] The present invention also provides use of the above composition in preparing therapeutic drug preparations or medical devices.

[0051] According to an embodiment of the present invention, the pharmaceutical preparation and medical device are used to treat endometriosis.

[0052] According to an embodiment of the present invention, the pharmaceutical preparation may be an injection.

[0053] According to an embodiment of the present invention, the medical device is a kit.

[0054] The present invention also provides a kit comprising the composition.

[0055] According to an embodiment of the present invention, the kit further comprises a container for containing the composition, such as a first container and a second container, or a single container such as a prefilled syringe.

[0056] According to an embodiment of the present invention, the first container is used to hold the dienogest; the second container is used to hold a biodegradable thermoplastic polymer and a polar aprotic organic liquid, preferably a mixture of N-methylpyrrolidone and a lactide-co-glycolide copolymer, N-methylpyrrolidone and polylactide, or dimethyl sulfoxide and polylactide and a lactide-co-glycolide copolymer. Preferably, the first container is connectable to the second container.

[0057] 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.

[0058] 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.

[0059] 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;

[0060] In some embodiments, the disease is endometriosis.

[0061] The percentages of components in the compositions and preparations of the present application, wt.%, wt% and %, all represent percentages by mass.

[0062] The term "plurality" refers to two or more, for example, two, three or more.

[0063] 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.

[0064] The term "therapeutically effective amount" refers to that amount of an active compound or drug that will elicit 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) prevent disease: e.g., prevent a disease, disorder, or condition in an individual who is susceptible to the disease, disorder, or condition but who is not yet experiencing or developing the pathology or symptoms of the disease. (2) inhibit disease: e.g., inhibit the disease, disorder, or condition (i.e., prevent 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) alleviate disease: e.g., alleviate the disease, disorder, or condition (i.e., reverse the pathology and / or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder, or condition. Beneficial effects

[0065] 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 injection volume; (b) good tissue tolerance at the injection site; (c) better release kinetics with minimal burst release; (d) extended drug release duration at a less frequent injection frequency; (e) good stability; and (f) a simple preparation process, relatively low difficulty in aseptic control, and ease of industrialization. BRIEF DESCRIPTION OF THE DRAWINGS

[0066] FIG1 is a pharmacokinetic curve diagram of an estradiol composition;

[0067] FIG2 is a pharmacokinetic curve of the dienogest composition in rats.

[0068] FIG3 is a pharmacokinetic curve of the dienogest composition in beagle dogs.

[0069] FIG4 is a graph showing changes in endometrial volume before and after administration of the dienogest composition to rats.

[0070] FIG5 is a graph showing changes in endometrial weight before and after administration of the dienogest composition to rats.

[0071] FIG6 is a graph showing the body weight change trend of rats before and after administration of the dienogest composition. DETAILED DESCRIPTION

[0072] The technical solutions of the present invention will be described in further detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative 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 encompassed within the scope of protection that the present invention is intended to protect.

[0073] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0074] Table A

[0075] Taking lactide-glycolide copolymer (5050) as an example, it represents a lactide-glycolide copolymer with a molar ratio of lactide to glycolide of 50:50.

[0076] Example 1 Preparation of Fulvestrant Composition

[0077] Table 1. Fulvestrant composition prescription

[0078] Dissolve the lactide-co-glycolide copolymer in a polar aprotic organic liquid until the polymer solution is clear and transparent, and add the prescribed amount of fulvestrant to the above polymer solution and mix until the active ingredient is evenly distributed.

[0079] This example aimed to prepare a long-acting fulvestrant composition and investigate the effects of different PLGA types, end groups, and solvents on the formulation. However, it was found that after adding fulvestrant, the solution rapidly separated into two phases, making it impossible to prepare a uniform formulation.

[0080] Example 2 Preparation of estradiol composition

[0081] Table 2. Estradiol composition prescription

[0082] Dissolve the lactide-co-glycolide copolymer in NMP until the polymer solution is clear and transparent, and add the prescribed amount of estradiol to the above polymer solution and mix until the active ingredients are evenly distributed.

[0083] Effect Example 1 Pharmacokinetic Study of Estradiol Long-Acting Composition in Rats

[0084] Test sample 1: Estradiol gel was prepared according to Preparation 5, with a concentration of 0.8 mg / ml.

[0085] Test sample 2: Estradiol gel was prepared according to Preparation 6, with a concentration of 0.8 mg / ml.

[0086] Reference substance: commercially available estradiol tablets (Abbott Healthcare Products BV), specification 1 mg.

[0087] Experimental animals: Sprague Dawley rats (SPF grade), male SD rats, aged 6-8 weeks, weighing 200-220 g, 6 rats per group, original source: Sprague Dawley (Beijing) Biotechnology Co., Ltd.; certificate number: 110324220107108468; production license number: SCXK (Beijing) 2019-0010.

[0088] Test steps:

[0089] (1) Grouping and experimental design are detailed in Table 3 below.

[0090] Table 3. Estradiol pharmacokinetics and dosing regimens

[0091] Note: The oral bioavailability of the reference substance is 5%

[0092] (2) Sample collection

[0093] 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.

[0094] 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.

[0095] Group 3: Blood samples were collected after oral gavage at 0 h (before dosing) and 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after dosing for measurement of estradiol plasma concentrations. Blood samples were placed in heparinized blood collection tubes and centrifuged to separate plasma (4000 rpm, 10 min, 2-8°C). Plasma samples were stored at -40°C until sample delivery. Plasma drug concentrations were determined by HPLC-MS / MS.

[0096] Table 4. Estradiol PK parameters in rat plasma

[0097] Table 5. Estradiol blood concentration

[0098] As shown in Table 4-5 and Figure 1, the long-acting composition of estradiol has obvious burst release. max 83.30ng / ml and 100.36ng / ml, and the reference tablet C max At 0.11 ng / ml, the burst release from the gel is 757-912 times that of the tablet, and dose dumping may pose safety concerns. Therefore, safety issues must be given high priority for long-acting preparations.

[0099] Example 3 Preparation of Dienogest Composition

[0100] Dissolve the lactide-co-glycolide copolymer in NMP until the polymer solution is clear and transparent. Add the prescribed amount of dienogest to the polymer solution and mix until the active ingredient is evenly distributed. Fill the product into a prefilled syringe. Remove the protective cap and connect the needle with a protective device for direct subcutaneous injection.

[0101] Table 6. Dienogest composition preparation formula

[0102] The dienogest compositions prepared in Table 6 were all uniform, transparent, or white to milky white preparations.

[0103] Example 4 Stability Study of Injectable Composition

[0104] To investigate the stability of the dienogest injectable composition, the preparations prepared in Table 7 were filled into prefilled syringes. The samples were stored at 2-8°C for 6 months to investigate changes in dienogest content, related substances, and molecular weight of the lactide-co-glycolide copolymer.

[0105] Table 7. Dienogest composition preparation formula

[0106] Table 8. Dienogest composition stability data

[0107] As shown in Table 8, the dienogest sample has good stability. After being stored 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.

[0108] Example 5: Results of Release Studies on Injectable Compositions

[0109] Six formulations (Formulations 13-18, shown in Table 9) were studied in rats for 0.5 and 24 hours (dosing schedules shown in Table 10) to ensure controlled burst release, investigate formulation safety, and screen the effects of drug loading, polymer concentration, lactide-to-glycolide ratio, and polymer end-capping. The results are shown in Tables 11 and 12.

[0110] Table 9. Dienogest Composition Prescription

[0111] Table 10. Dosing regimen for dienogest composition release studies

[0112] Table 11. 0.5h Dienogest Plasma Levels from Dienogest Compositions

[0113] Table 12. 24h Dienogest Release from Dienogest Compositions

[0114] in conclusion:

[0115] 1. As the drug loading decreases, the average plasma concentration in 0.5 hours tends to increase, and the average release value in 24 hours increases, indicating that the lower the drug loading, the higher the burst release.

[0116] 2. The 0.5h mean plasma concentration and 24h mean release values ​​of formulation 14 were lower than those of formulation 18, indicating that the higher the polymer concentration, the lower the burst release of dienogest.

[0117] 3. The 0.5h mean plasma concentration and 24h mean release values ​​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.

[0118] 4. For preparations with the same formula 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 groups had little effect on the release.

[0119] In summary, we found that initial release depends on polymer concentration (higher concentrations result in lower burst release of dienogest), drug loading (higher drug loading results in lower burst release), and the lactide-to-glycolide ratio (higher lactide ratios result in lower burst release). Differences between carboxyl and ester end groups have little effect on release. A drug loading of 16.7% is the preferred formulation.

[0120] Example 6. Pharmacokinetics of Dienogest Long-Acting Composition in Rats

[0121] (1) Preparation Example

[0122] Table 13. Dienogest Composition Prescription

[0123] According to Table 13, the prescribed amount of lactide-co-glycolide copolymer and NMP were weighed into a small tank of a centrifugal defoamer and mixed at 2200 rpm for 5-10 min. The prescribed amount of dienogest was added and mixed at 2200 rpm for 10-20 min to obtain preparations 13-15.

[0124] (2) Effect examples

[0125] Test drugs: Preparations 13, 14, and 15.

[0126] Reference substance: Commercially available dienogest tablets: Visanning, specification 2 mg (Jenapharm GmbH & Co. KG).

[0127] Experimental animals: Sprague Dawley rats (SPF grade), female SD rats, aged 8-9 weeks, weighing 200-220 g, 7 rats per group.

[0128] Test steps:

[0129] Table 14. Grouping and experimental design Note: The oral bioavailability of the reference product is 91%.

[0130] Collect samples

[0131] 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.

[0132] 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.

[0133] 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%.

[0134] Plasma: Collect 0.4 mL of whole blood via the jugular vein of rats at each sampling time point. Store the EP tube upright at 2-8°C. Centrifuge (4000 rpm, 2-8°C, 10 min). Then, collect the plasma and aliquot it into two 100 μL aliquots plus a backup. Store the separated plasma at -40°C. Determine drug concentration in plasma by HPLC-MS / MS.

[0135] Table 15. Pharmacokinetic data of dienogest Note: / indicates that blood was not drawn at this point

[0136] Table 16. Dienogest PK parameters in rat plasma

[0137] Table 16 shows that the control group was given 5 consecutive days of Tiannogest tablets. min -C max The range of C was 0.35-385.14 ng / ml. The data showed that the initial burst release of the three groups of dienogest injectable compositions tested (i.e., formulations 13-15) was C max At 118.54~136.04ng / ml, both lower than Tablet C max , indicating that the safety of the dienogest combination preparation is good.

[0138] Table 15 and Figure 2 show that in the test groups of formulations 13-15, quantifiable concentrations of dienogest were present in all the rats tested on day 35. During the entire 42-day dosing cycle, the plasma concentration of the dienogest injectable composition was within the range of the tablet C min -C max It is found that the carboxyl end capping and ester end capping of the copolymer will affect the bioavailability AUC of the preparation. last , AUC of Formulation 13 and Formulation 14 last In contrast, the results showed that the AUC of the carboxyl-terminated copolymer preparation last The molar ratio of lactide affects the release period of the preparation (release period evaluation index: T 1 / 2 ), considering the release period of one month, the carboxyl-terminated lactide-co-glycolide copolymer (5050) is preferred.

[0139] Example 7. Pharmacokinetic Study of Dienogest Long-Acting Composition in Beagle Dogs

[0140] (1) Preparation Example

[0141] Table 17. Dienogest Composition Prescription

[0142] 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, and the mixture was mixed at 2200 rpm for 5-10 min. The prescribed amount of dienogest was added and mixed at 2200 rpm for 10-20 min to obtain formulations 19-22.

[0143] (2) Effect examples

[0144] Test drugs: Preparations 19, 20, 21, and 22.

[0145] Reference substance: Commercially available dienogest tablets: Visanning, specification 2 mg (Jenapharm GmbH & Co. KG).

[0146] Experimental animals: Beagle dogs, female, aged 8-11 weeks, weighing 8-14 kg, 6 dogs per group.

[0147] Test steps:

[0148] Table 18. Grouping and experimental design Note: The oral bioavailability of the reference product is 91%.

[0149] Collect samples

[0150] 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.

[0151] 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.

[0152] 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%.

[0153] Plasma: 1 mL of whole blood was collected from the dog's cephalic vein at each sampling time point. The EP tube was stored upright at 2-8°C and centrifuged (4000 rpm, 2-8°C, 10 min). Plasma was collected and divided into 250 μl aliquots. The separated plasma was stored at -80°C. Drug concentrations in plasma were determined by HPLC-MS / MS.

[0154] The test results are shown in Figure 3, Table 19, and Table 20.

[0155] Table 19. Dienogest blood concentration Note: / indicates that blood was not drawn at this point

[0156] Table 20. Dienogest PK parameters in beagle dog plasma

[0157] Preparations 19-22 long-acting preparations have stable blood drug concentration release, long-acting preparations C max Lower than Tablet C max , and there was no rapid or unexplained increase in exposure, proving the safety of the preparation; the long-acting group significantly prolonged the half-life, T 1 / 2 For tablets T 1 / 2 The plasma concentration of dienogest tablets C during the entire administration period was 69.5-176.9 times that of min ~C max The blood concentration of the group with ester-terminated lactide-co-glycolide copolymer (7525) (preparation 21 / 22 group) showed an upward trend from 56 to 84 days compared with the group without addition (preparation 20). As of 84 days, the AUC of each long-acting preparation group was 74.2% to 101.1% of the oral group, which was 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.

[0158] Example 8. Pharmacodynamics test of long-acting dienogest composition in rats

[0159] To evaluate the efficacy of long-acting dienogest formulations 19, 20, and 22 in endometriosis model rats after subcutaneous injection.

[0160] The experimental design is as follows:

[0161] Normal female rats underwent endometriosis or sham surgery according to the following schedule: after anesthesia with Zota-50, laparotomy was performed, the right uterus of the ligated segment was excised and freed, the endometrium and myometrium were separated, and two pieces of endometrial tissue (approximately 5 mm × 5 mm) were cut. The epithelial layer of the endometrium was reversed to face the left abdominal wall and fixed by suture or gluing; for sham surgery, laparotomy was performed after anesthesia, the right uterus of the ligated segment was excised and freed, and then sutured.

[0162] 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. Patients were grouped according to the endometrial cyst volume and body weight. After laparotomy, postoperative care was started three days later. Specific grouping information is shown in Table 21.

[0163] Table 21. Animal grouping information

[0164] Dosage:

[0165] Number of animals: 6 animals per group. The animals were divided into groups according to the cyst volume and body weight before administration.

[0166] Animal weighing: The animals were weighed and recorded before administration and twice a week after administration.

[0167] Fasting requirements: All animals were allowed to eat and drink freely before administration.

[0168] Administration: DNG table was administered orally by gavage, and formulations 19, 20, and 22 were administered subcutaneously (due to the high viscosity of the formulations, the dosage was verified by weighing the syringe containing the drug before and after administration to each animal).

[0169] Dosing frequency: G3-G4 were given once a day; the other groups received a single subcutaneous injection.

[0170] Calculation of dosage: dosage (mL) = animal body weight (kg) * dosage volume (mL / kg).

[0171] Evaluation indicators:

[0172] Animal weighing: The animals were weighed and recorded before administration and twice a week thereafter.

[0173] Endometrial cyst volume measurement:

[0174] The animals were anesthetized on D0, D42, and D84, and the abdomen was opened 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.

[0175] Endometrial cyst wet weight:

[0176] On D84, all animals were euthanized, and the endometrial cysts were removed and weighed.

[0177] Take a photo of the uterus:

[0178] Before and after surgery, on D84, the animals were anesthetized and opened to examine the uterus (N=10).

[0179] The results are as follows (see Figures 4, 5, and 6): Endometrial retraction was observed to varying degrees across groups G5-G7, with no significant differences observed. The efficacy was maintained for 3 months in all groups. There was no significant effect on animal body weight after 84 days of dosing. Analysis of endometrial volume and weight trends showed comparable results between Formulations 19 and 20, with Formulation 19 showing superior results and comparable efficacy to the tablet group.

[0180] Example 9. Preparation of a double-pack of dienogest composition

[0181] Dissolve the lactide-co-glycolide copolymer in NMP solvent until the polymer solution is clear and transparent, and fill the solution into a female syringe. The syringe can be sterilized by filtration or terminal irradiation with gamma rays.

[0182] The dienogest powder is filled into a male syringe. The powder is either sterile lyophilized or sterilized by irradiation after filling. Prior to injection, the product is reconstituted by connecting two syringes and mixing by reciprocating the plunger. After multiple cycles of mixing, the powder is completely dissolved in the polymer solution. After thorough mixing, the formulation is withdrawn into the female syringe, connected to a protected needle, and the final subcutaneous injection is completed, with an injection volume of <1 mL.

[0183] Table 22. Dienogest Composition Prescription

[0184] Table 23. Investigation of the number of times the composition preparation is mixed

[0185] Conclusion: The double-packed preparation can meet the content uniformity requirement by mixing more than 200 times before injection.

[0186] It can be seen that the single or double-packed dienogest long-acting delivery injectable composition is prepared, and the preparation has good physical and chemical 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 within the C of the tablet. min -C max At the same time, the blood drug concentration can be maintained for about 84 days, which proves 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.

[0187] The above describes the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included in the scope of protection of the present invention.

Claims

1. A composition, characterized in that The composition comprises: (a) a biodegradable thermoplastic polymer; (b) a polar aprotic organic liquid; and (c) dienogest.

2. 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); Preferably, when the biodegradable thermoplastic polymer is selected from the above two polymers, the mass ratio of the two is (1-7):

1.

3. The composition according to claim 1 or 2, characterized in that The polylactide or lactide-glycolide copolymer is carboxyl or ester terminated; And / or, the molar ratio of lactide to glycolide in the lactide-glycolide copolymer is (50-85):(50-15); 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; And / or, the biodegradable thermoplastic polymer has an average molecular weight of 10,000 Daltons to 45,000 Daltons.

4. 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, wherein the molar ratio of lactide to glycolide is 50:50, 75:25 or 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.

5. 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; 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.

6. 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; 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; 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.

7. The composition according to any one of claims 1 to 6, characterized in that The volume of the composition is from about 0.20 mL to about 2.0 mL; and / or, the composition is a flowable composition, such as a gel; and / or, the composition is a stable sustained-release composition, which is a subcutaneously injectable durable sterile composition suitable for forming an in situ solid, semisolid or gel implant in the body of a subject; 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.

8. Use of the composition according to any one of claims 1 to 7 in the preparation of therapeutic drug preparations or medical devices; Preferably, the pharmaceutical preparation and medical device are used to treat endometriosis; Preferably, the pharmaceutical preparation is an injection, and the medical device is a kit.

9. A kit, characterized in that: The kit comprises the composition according to any one of claims 1 to 7.

10. 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 prior to administration; Alternatively, the method comprises mixing the mixture of the biodegradable thermoplastic polymer and the polar aprotic organic liquid with dienogest prior to administration.

11. A method for treating a disease caused by hormone imbalance in women, characterized in that: The method of treatment comprises administering a therapeutically effective amount of the composition of any one of claims 1 to 7 to a patient in need thereof.

12. The method of claim 11, characterized in that The disease is endometriosis.

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