Estrogen-containing subcutaneous implant and its preparation method

Abstract

The present invention relates to a subcutaneous implant for hormone replacement therapy, comprising a shell and a core. The shell wraps around the outside of the core and is columnar as a whole. The shell comprises estrogen and a biodegradable polymer, and the core comprises an estrogen receptor inhibitor and a biodegradable polymer. When implanted into the body, the estrogen in the shell starts to continuously and stably release a fixed amount of drug daily. As the drug in the shell dissolves and diffuses and the material degrades, the active drug in the core gradually and slowly releases after a certain period of drug administration, realizing sequential combined administration of two active substances in a single implant.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical preparations, and more particularly, to a subcutaneous implant and a preparation method thereof. Background Art

[0002] Perimenopause refers to the period from the beginning of ovarian function decline to one year after menopause in women. During perimenopause and after menopause, estrogen secretion gradually decreases due to follicle exhaustion and ovarian function decline in the ovaries of women, leading to a series of physiological and pathological changes. Physiological changes include changes in secondary sexual characteristics, vulvar atrophy, vaginal atrophy, senile vaginitis, urinary system symptoms such as frequent urination, urgency, stress urinary incontinence, atrophy of the pelvic floor muscles of the uterus and vaginal wall prolapse; skin relaxation and inelasticity, dryness and easy damage, dry mouth, dryness of the conjunctiva of the eyes, etc. Pathological changes are manifested as perimenopausal menstrual disorders, perimenopausal syndrome, cardiovascular diseases (such as coronary heart disease, hypertension, atherosclerosis, etc.), osteoporosis, genital tract tumors (such as uterine tumors, endometrial cancer, cervical cancer, etc.). There are also some easily overlooked symptoms, such as hot flashes, night sweats, mood changes, memory decline, insomnia, etc.

[0003] Currently, estrogen replacement therapy (ERT) is mostly adopted clinically, that is, a treatment method of treating diseases caused by hormone secretion reduction or deficiency by supplementing hormones to relieve health problems related to perimenopause. The common administration methods of hormone therapy can be divided into oral route, transdermal route (such as dosage forms like gels, ointments, patches, etc.), transvaginal route and subcutaneous implantation route.

[0004] Oral preparations have the longest survival time and the widest range, but have the following disadvantages: (1) Low patient compliance. Since patients need to take drugs regularly for a long time, and accompanied by the current situation of easy memory decline during perimenopause, patients are prone to not taking drugs on time or even forgetting to take drugs; (2) Oral medications need to be administered frequently, and the blood drug concentration fluctuates greatly. In order to ensure the drug effect for a certain period of time in the future, a large amount of active drugs need to be added to oral preparations. The liver metabolism of high-dose estrogen will not only damage the liver, but also increase the probability of patients getting coronary heart disease, venous thromboembolism and stroke.

[0005] The transdermal route and the transvaginal route can avoid the first-pass effect of the liver, but also have the following deficiencies: (1) The dosage frequency of gel and ointment preparations is relatively high, and the dosage and the skin area for topical use are not standardized, making it difficult for patients to control; (2) The replacement frequency of patch preparations is reduced and the drug release is relatively stable, but long-term use is likely to cause skin irritation problems. At the same time, patches have certain requirements for skin humidity, and their adhesion gradually weakens with the increase of use time; (3) Transvaginal administration is likely to cause vaginal flora imbalance, vaginal dryness, drug resistance, and even cause other gynecological diseases.

[0006] The subcutaneous implantation route can provide relatively lower and more stable serum estrogen levels, and has a longer administration cycle. However, continuous estrogen release may increase the risks of endometrial hyperplasia and cancer. Therefore, there is a clinical need for a drug delivery method that can continuously administer drugs with fewer side effects. Summary of the Invention

[0007] One aspect of the present invention is to provide a subcutaneous implant that can continuously supplement estrogen with fewer side effects.

[0008] The subcutaneous implant of the present application has an overall columnar structure and includes an outer shell and an inner core. The outer shell includes estrogen and a biodegradable polymer, and the inner core includes an estrogen receptor inhibitor and a biodegradable polymer.

[0009] The estrogen includes natural estrogen and synthetic estrogen. The natural estrogen includes estradiol, estrone, and estriol; the synthetic estrogen includes ethinylestradiol, estradiol valerate, estradiol benzoate, quinestrol, ethinylestradiol 3-methyl ether, conjugated estrogens, nilestriol, diethylstilbestrol, hexestrol, and clomiphene. The estrogen of the present application is selected from one or more of them.

[0010] The estrogen receptor inhibitor includes a selective estrogen receptor downregulator and a selective estrogen receptor modulator. The selective estrogen receptor downregulator includes fulvestrant, AZD9496 and its derivatives; the selective estrogen receptor modulator includes tamoxifen, raloxifene, lasofoxifene, and phytoestrogens; the phytoestrogens include coumestrol, genistein, daidzein, and isoflavones. The estrogen receptor inhibitor of the present application is selected from one or more of them.

[0011] The biodegradable polymer includes a lactide-glycolide copolymer (PLGA). The PLGA is a mixture of uncapped and capped PLGA, and the mass percentage ratio of the uncapped PLGA polymer to the capped PLGA polymer is 1:3 to 5:1.

[0012] In some embodiments, the mass ratio of estrogen to the estrogen receptor inhibitor is 1:3 to 1:6.

[0013] In some embodiments, the mass percentage ratio of lactide (LA) to glycolide (GA) in PLGA is 50:50 to 60:40, where the content of polymers with an average molecular weight of more than 60,000 accounts for more than 85%, and the content of polymers with an average molecular weight of less than 5,000 accounts for less than 15%.

[0014] In some embodiments, the polymer with an average molecular weight of 80,000 in the lactide-glycolide copolymer in the outer shell accounts for 90%, and the content of polymers with an average molecular weight of less than 5,000 accounts for 10%.

[0015] In some embodiments, 85% of the polylactide-glycolide copolymer in the core has an average molecular weight of 60,000, and 15% of the polymer has a content with an average molecular weight of less than 5,000.

[0016] In some embodiments, the subcutaneous implant further comprises a release enhancer.

[0017] Optionally, the release enhancer comprises one or more of hydroxypropyl cellulose, polyethylene glycol, and poloxamer.

[0018] Another aspect of the present invention also provides a method for preparing a subcutaneous implant:

[0019] First, the estrogen, estrogen receptor inhibitor, and degradable polymer are respectively passed through a 100-mesh sieve and reserved for use;

[0020] Secondly, heat the barrel of the plunger extruder;

[0021] Then, the estrogen and the degradable polymer are mixed evenly and put into hopper one for compaction, and the estrogen receptor inhibitor and the degradable polymer are mixed evenly and put into hopper two for compaction;

[0022] Finally, the two hoppers are extruded simultaneously, and the obtained extrudate is in a columnar structure, more specifically, a rod-like structure or a cylindrical structure.

[0023] Optionally, the extrusion speed is 2 - 4 mm / min, and the pressure is 400 - 600 Mpa.

[0024] Furthermore, the barrel of the plunger extruder is heated to 110 °C. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] In order to more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the following will briefly introduce the drawings required for use in the description of the specific embodiments or the prior art. Obviously, the drawings in the following description are some embodiments of the present invention. For those of ordinary skill in the art, other drawings can be obtained based on these drawings without creative efforts.

[0026] Figure 1 It is the in vitro drug release rate graph of Example 1 of the present invention;

[0027] Figure 2 It is the in vitro drug cumulative release degree graph of Example 1 of the present invention;

[0028] Figure 3 It is the in vitro drug cumulative release degree graph of Example 2 of the present invention;

[0029] Figure 4It is the in vitro drug cumulative release degree graph of Example 3 of the present invention;

[0030] Figure 5 It is the in vitro drug cumulative release degree graph of Example 4 of the present invention;

[0031] Figure 6 It is the in vitro drug cumulative release degree graph of Example 5 of the present invention;

[0032] Figure 7 It is the oral tablet drug cumulative release degree graph of Comparative Example 2 of the present invention. Detailed Description

[0033] Reference will now be provided in detail to embodiments of the present invention, one or more examples of which are described below. Each example is provided by way of explanation and not limitation of the present invention. In fact, it will be apparent to those skilled in the art that various modifications and variations can be made to the present invention without departing from the scope or spirit of the present invention. For example, features illustrated or described as part of one embodiment can be used in another embodiment to yield a still further embodiment.

[0034] Accordingly, it is intended that the present invention cover such modifications and variations that fall within the scope of the appended claims and their equivalents. Other objects, features, and aspects of the present invention are disclosed in the following detailed description or are apparent therefrom. Those of ordinary skill in the art should understand that this discussion is only a description of exemplary embodiments and is not intended to limit the broader aspects of the present invention.

[0035] In the present invention, among the technical features described in an open-ended manner, there are included closed technical solutions composed of the listed features, as well as open technical solutions containing the listed features.

[0036] In the present invention, regarding numerical ranges, unless otherwise specified, the above numerical ranges are considered continuous and include the minimum value and the maximum value of the range, as well as each value between such minimum and maximum values. Further, when the range refers to integers, it includes each integer between the minimum and maximum values of the range. In addition, when multiple ranges are provided to describe features or characteristics, the ranges can be combined. In other words, unless otherwise indicated, all ranges disclosed herein should be understood to include any and all sub-ranges subsumed therein.

[0037] In this article, for units related to data ranges, if only the unit is attached after the right endpoint, it means that the units of the left endpoint and the right endpoint are the same. For example, 10~15mg means that the units of the left endpoint "10" and the right endpoint "15" are both mg (milligrams).

[0038] The present invention relates to a subcutaneous implant, which is in a columnar structure as a whole and includes a shell and a core; the shell wraps around the outside of the core and the two are tightly connected. The shell includes estrogen and a biodegradable polymer, and the core includes an estrogen receptor inhibitor and a biodegradable polymer. Since the biodegradable polymer is a hydrophilic material, after encountering water, the shell starts to release the hormone it contains first, and as time goes by, the core starts to release later after encountering water, thus realizing the sequential administration of the two hormones.

[0039] The present invention aims to treat diseases caused by reduced or lack of estrogen secretion by hormone replacement therapy through supplementing estrogen. The commonly used estrogen at present is estradiol. Considering that the continuous release of estradiol may increase the risks of endometrial hyperplasia and cancer, for women with a uterus, it is necessary to continuously use additional cyclic progesterone monthly. Therefore, estradiol will not be used in both the shell and the core at the same time.

[0040] Estrogen includes natural estrogen and synthetic estrogen, and synthetic estrogen can be divided into semi-synthetic estrogen and synthetic estrogen.

[0041] Natural estrogen includes: estradiol, estrone, estriol, etc.

[0042] Semi-synthetic estrogen includes: ethinylestradiol, estradiol valerate, estradiol benzoate, quinestrol, ethinylestradiol, conjugated estrogens (premarin), nilestriol (i.e., pentynylestradiol), etc.

[0043] Synthetic estrogen includes: non-steroidal estrogen, mainly diethylstilbestrol, hexestrol, and chlorotrianisene, etc.

[0044] Estrogen receptor inhibitors include selective estrogen receptor downregulators and selective estrogen receptor modulators. Among them, selective estrogen receptor downregulators include fulvestrant, AZD9496 and its derivatives, etc. These drugs can significantly downregulate the level of estrogen receptor protein. Selective estrogen receptor modulators are a group of non-steroidal compounds with tissue-selective action mechanisms, which only have an agonist effect on one estrogen receptor (ER) subtype, ERα or ERβ, and have no effect or an antagonist effect on the other subtype. Their "selectivity" means that selective estrogen receptor modulators act as agonists in some tissues such as bone, liver, and cardiovascular system, while acting as antagonists in other tissues such as breast. They can be agonists or antagonists in the uterus, can replace progesterone, improve the drug tolerance of existing progesterone, reduce the risks of breast cancer, breast pain, and vaginal bleeding, and treat menopausal symptoms. They mainly include tamoxifen, raloxifene, lasofoxifene, and phytoestrogens, etc.

[0045] Phytoestrogens include coumestrol, genistein, daidzein, and isoflavones, etc. Among them, genistein is a natural isoflavone phytoestrogen found in leguminous plants. Its molecular structure is similar to 17β-estradiol, and it has the characteristics of tissue-specific antagonists and agonists. Genistein can reduce menopausal symptoms such as hot flashes. It has an agonist and positive effect on bone cells, and has no obvious adverse effects on the breast and uterus.

[0046] In some embodiments, the mass ratio of estrogen to estrogen receptor inhibitor in the subcutaneous implant is 1:3 to 1:6.

[0047] The present invention uses a biodegradable polymer, which does not need to be removed after use, reduces secondary harm to the body, does not have the problems of forgetting to take medicine and poor dependence, and has high patient compliance. The biodegradable polymer includes poly(lactic-co-glycolic acid) (PLGA), and PLGA is a mixture of uncapped and capped PLGA. The mass percentage ratio of uncapped PLGA polymer to capped PLGA polymer is 1:3 to 5:1. The capped PLGA polymer mainly refers to the ester group-capped one, and the uncapped PLGA polymer mainly refers to the carboxyl group-capped one. The terminal carboxyl group in the PLGA chain has stronger hydrophilicity and there is an autocatalytic degradation process. Therefore, the carboxyl group-capped PLGA polymer degrades faster in water, and the capping in the chain prolongs the degradation time.

[0048] As used herein, "ester group-capped polymer" or "ester group-capped copolymer" means that the end group of the polymer or copolymer is an ester bond. The ester group-capped copolymer has lower polarity, poorer hydrophilicity, and longer degradation time.

[0049] As used herein, "carboxyl group-capped polymer" or "carboxyl group-capped copolymer" means that the end group of the polymer or copolymer is a carboxyl group. The carboxyl group-capped copolymer has higher polarity, stronger hydrophilicity, and shorter degradation time.

[0050] PLGA is polymerized from lactic acid (LA) and glycolic acid (GA). By adjusting the ratio and molecular weight of LA and GA, the hydrophilicity and degradation rate of PLGA can be adjusted. In the present invention, the mass percentage ratio of LA to GA is 50:50 to 60:40, among which the content of polymers with an average molecular weight of more than 60,000 accounts for more than 85%, and the content of polymers with an average molecular weight of less than 5,000 accounts for less than 15%. The administration period is one month.

[0051] In some embodiments, in the PLGA of the outer shell, the polymer with an average molecular weight of 80,000 accounts for 90%, and the content of polymers with an average molecular weight of less than 5,000 accounts for 10%. In the PLGA of the inner core, the polymer with an average molecular weight of 60,000 accounts for 85%, and the content of polymers with an average molecular weight of less than 5,000 accounts for 15%.

[0052] In some embodiments, the subcutaneous implant further includes a release enhancer, which includes one or more of hydroxypropyl cellulose, polyethylene glycol, and poloxamer.

[0053] Each implant is configured with an independent sterilized prefilled syringe. The implant is stored in the injection needle and slowly pushed in during use to achieve subcutaneous implantation, which can avoid metabolic stress on the liver while maintaining high drug efficacy. A single implant simulates the physiological cycle, and the dosing cycle is maintained for one month. Since the implant is placed in the body, the outer shell continuously and stably releases a fixed amount of estrogen daily. As the drugs in the outer shell dissolve and diffuse and the material degrades, the core active drug gradually and slowly releases after a certain period of drug administration, realizing sequential combined administration of two active substances in a single implant. By continuous implantation or cyclic implantation, the drug can be released to simulate the premenopausal physiological cycle of women.

[0054] Another aspect of the present invention also provides a method for preparing a subcutaneous implant:

[0055] First, estradiol valerate, an estrogen receptor inhibitor, and a biodegradable polymer are each passed through a 100-mesh sieve three times for standby;

[0056] Secondly, the barrel of the plunger extruder is heated to 110 °C;

[0057] Then, estradiol valerate and the biodegradable polymer are mixed evenly and placed in hopper one for compaction, and the estrogen receptor inhibitor and the biodegradable polymer are mixed evenly and placed in hopper two for compaction;

[0058] Finally, the two hoppers are extruded simultaneously, and the obtained extrudate is in a columnar structure, more specifically, a rod-like structure or a cylindrical structure.

[0059] Optionally, the extrusion speed is 3 mm / min and the pressure is 400 - 600 Mpa.

[0060] This preparation method is simple and easy to operate. The dosage of each component can be adjusted to meet the medication needs of different patients, achieving the effect of flexible dosing. In the form of a subcutaneous implant, it can maintain a relatively stable blood drug concentration in the patient's body, improve medication safety, and also avoid problems such as patients forgetting to take medicine or taking the wrong dose.

[0061] The embodiments of the present invention will be described in detail below in conjunction with the examples.

[0062] In a non-limiting embodiment of the present invention, the subcutaneous implant includes an outer shell and a core, and the active ingredients include estradiol valerate and genistein. The mass ratio of estradiol valerate to genistein is 1:3 - 1:5.

[0063] The outer shell is composed of estradiol valerate and the biodegradable polymer PLGA, where the mass percentage ratio of estradiol valerate to PLGA is 45:55. In PLGA, the mass percentage ratio of lactide (LA) to glycolide (GA) is LA:GA = 60:40. Regarding the molecular weight of PLGA, the mass percentage ratio of the polymer with an average molecular weight of 80,000 Daltons is approximately 90%, and the mass percentage ratio of the polymer with an average molecular weight of 5,000 Daltons or less is approximately 10%.

[0064] The core is composed of genistein and the biodegradable polymer PLGA. In the core, the mass percentage ratio of genistein to PLGA is 45:55. In PLGA, the mass percentage ratio of lactide to glycolide is LA:GA = 50:50. Regarding the molecular weight, the mass percentage ratio of the polymer with an average molecular weight of 60,000 Daltons is approximately 85%, and the mass percentage ratio of the polymer with an average molecular weight of 5,000 Daltons or less is approximately 15%.

[0065] The specific contents of each component are shown in Table 1 below:

[0066] Table 1: The shell-core components and their contents of Examples 1 - 5

[0067]

[0068] Subcutaneous implants were prepared according to the groups in the above table. Taking Example 1 as an example, the active ingredient estradiol valerate, PLGA (LA:GA = 60:40), genistein, and PLGA (LA:GA = 50:50) were each passed through a 100-mesh sieve three times and reserved. Then, the barrel of the plunger extruder was heated to 110°C. 5 mg of estradiol valerate was taken and mixed evenly with 6.1 mg of PLGA (LA:GA = 60:40), and then transferred to Hopper 1 and compacted; 20 mg of genistein was taken and mixed evenly with 24.4 mg of PLGA (LA:GA = 50:50), and then transferred to Hopper 2 and compacted. Then, the mixtures in the two hoppers were extruded simultaneously at an extrusion speed of 3 mm / min and an extrusion pressure of 500 Mpa. The extrudate obtained was a columnar structure, more specifically a rod-like structure.

[0069] The estradiol valerate content of the extrudate was tested by liquid chromatography. According to the theoretically designed drug content in the experiment, the mass of the subcutaneous implant could be calculated. Based on this, the diameter and length of the subcutaneous implant were determined.

[0070] Examples 2 - 5 were prepared using the same preparation method as Example 1, and the parameters of the subcutaneous implants are shown in Table 2 below.

[0071] Table 2: Parameters of the subcutaneous implants of Examples 1 - 5

[0072]

[0073]

[0074] As can be seen from Table 2, the diameter range of the subcutaneous implants in Examples 1 to 5 is 1 to 2 mm, and the length range is 2 to 4 cm, which conforms to the size range of conventional subcutaneous implants.

[0075] In another group of non-limiting embodiments of the present invention, the active ingredients of the subcutaneous implant include estradiol and lasofoxifene, and the mass ratio of estradiol to lasofoxifene is 1:3 to 1:5. The outer shell is composed of estradiol and PLGA (LA:GA = 50:50), and the mass percentage content ratio of estradiol to PLGA is 45:55; regarding the molecular weight of PLGA, the mass percentage content ratio of the polymer with an average molecular weight of 80,000 daltons is about 90%, and the mass percentage content ratio of the polymer with an average molecular weight of 5,000 daltons or less is about 10%. The inner core is composed of lasofoxifene and PLGA (LA:GA = 50:50), and the mass percentage content ratio of lasofoxifene to PLGA is 45:55; regarding the molecular weight of PLGA, the mass percentage content ratio of the polymer with an average molecular weight of 60,000 daltons is about 85%, and the mass percentage content ratio of the polymer with an average molecular weight of 5,000 daltons or less is about 15%.

[0076] Using the same preparation method as in Example 1 and using the components and masses shown in Table 3 below, Examples 6 to 7 were prepared.

[0077] Table 3: Shell-core components and their contents of Examples 6 to 7

[0078]

[0079] The diameter range of the subcutaneous implants in Examples 6 to 7 is 0.5 to 2 mm, and the length range is 2 to 4 cm, which also conforms to the size range of conventional subcutaneous implants.

[0080] In another group of non-limiting embodiments of the present invention, the active ingredients of the subcutaneous implant include estradiol and fulvestrant, and the mass ratio of estradiol to fulvestrant is 1:3 to 1:6. The outer shell is composed of estradiol and PLGA (LA:GA = 50:50), and the mass percentage ratio of estradiol to PLGA is 50:50; regarding the molecular weight of PLGA, the mass percentage ratio of the polymer with an average molecular weight of 80,000 Daltons is about 90%, and the mass percentage ratio of the polymer with an average molecular weight of 5,000 Daltons or less is about 10%. The inner core is composed of fulvestrant and PLGA (LA:GA = 50:50), and the mass percentage ratio of fulvestrant to PLGA is 50:50; regarding the molecular weight of PLGA, the mass percentage ratio of the polymer with an average molecular weight of 60,000 Daltons is about 85%, and the mass percentage ratio of the polymer with an average molecular weight of 5,000 Daltons or less is about 15%.

[0081] Using the same preparation method as in Example 1 and using the components and masses shown in Table 4 below, Examples 8 to 9 were prepared.

[0082] Table 4: The shell and core components and their contents of Examples 8 to 9

[0083]

[0084] The diameter range of the subcutaneous implants in Examples 8 to 9 is also 0.5 to 2 mm, and the length range is 2 to 4 cm, which also conforms to the size range of conventional subcutaneous implants.

[0085] In another group of non-limiting embodiments of the present invention, the active ingredients of the subcutaneous implant include quinestrol and tamoxifen, and the mass ratio of quinestrol to tamoxifen is 1:3 to 1:5. Weigh 10 mg of quinestrol and 40 mg of tamoxifen. The outer shell is composed of quinestrol and PLGA (LA:GA = 60:40), and the mass percentage ratio of quinestrol to PLGA is 50:50. Weigh 10 mg of PLGA; regarding the molecular weight of PLGA, the mass percentage ratio of the polymer with an average molecular weight of 80,000 Daltons is about 90%, and the mass percentage ratio of the polymer with an average molecular weight of 5,000 Daltons or less is about 10%. The inner core is composed of tamoxifen and PLGA (LA:GA = 50:50), and the mass percentage ratio of tamoxifen to PLGA is 50:50. Weigh 40 mg of PLGA; regarding the molecular weight of PLGA, the mass percentage ratio of the polymer with an average molecular weight of 60,000 Daltons is about 85%, and the mass percentage ratio of the polymer with an average molecular weight of 5,000 Daltons or less is about 15%.

[0086] Using the same preparation method as in Example 1, Example 10 was prepared.

[0087] The diameter range of the subcutaneous implant of Example 10 is also 0.5 - 2 mm, and the length range is 2 - 4 cm, which also conforms to the size range of conventional subcutaneous implants.

[0088] In another group of non - restrictive embodiments of the present invention, the active ingredients of the subcutaneous implant include conjugated equine estrogens and raloxifene, and the mass ratio of conjugated equine estrogens to raloxifene is 1:3 - 1:5. Weigh 10 mg of conjugated equine estrogens and 40 mg of raloxifene. The outer shell is composed of conjugated equine estrogens and PLGA (LA:GA = 60:40), and the mass percentage content ratio of conjugated equine estrogens to PLGA is 50:50. Weigh 10 mg of PLGA; regarding the molecular weight of PLGA, the mass percentage content ratio of the polymer with an average molecular weight of 80,000 daltons is about 90%, and the mass percentage content ratio of the polymer with an average molecular weight of 5,000 daltons or less is about 10%. The inner core is composed of raloxifene and PLGA (LA:GA = 50:50), and the mass percentage content ratio of raloxifene to PLGA is 50:50. Weigh 40 mg of PLGA; regarding the molecular weight of PLGA, the mass percentage content ratio of the polymer with an average molecular weight of 60,000 daltons is about 85%, and the mass percentage content ratio of the polymer with an average molecular weight of 5,000 daltons or less is about 15%.

[0089] Using the same preparation method as in Example 1, Example 11 was prepared.

[0090] The diameter range of the subcutaneous implant of Example 11 is also 0.5 - 2 mm, and the length range is 2 - 4 cm, which also conforms to the size range of conventional subcutaneous implants.

[0091] In another group of non - restrictive embodiments of the present invention, the active ingredients of the subcutaneous implant include diethylstilbestrol and equilinolide, and the mass ratio of diethylstilbestrol to equilinolide is 1:3 - 1:5. Weigh 10 mg of diethylstilbestrol and 40 mg of equilinolide. The outer shell is composed of diethylstilbestrol and PLGA (LA:GA = 50:50), and the mass percentage content ratio of diethylstilbestrol to PLGA is 50:50. Weigh 10 mg of PLGA; regarding the molecular weight of PLGA, the mass percentage content ratio of the polymer with an average molecular weight of 80,000 daltons is about 90%, and the mass percentage content ratio of the polymer with an average molecular weight of 5,000 daltons or less is about 10%. The inner core is composed of equilinolide and PLGA (LA:GA = 50:50), and the mass percentage content ratio of equilinolide to PLGA is 50:50. Weigh 40 mg of PLGA; regarding the molecular weight of PLGA, the mass percentage content ratio of the polymer with an average molecular weight of 60,000 daltons is about 85%, and the mass percentage content ratio of the polymer with an average molecular weight of 5,000 daltons or less is about 15%.

[0092] Example 12 was prepared using the same preparation method as in Example 1.

[0093] The diameter range of the subcutaneous implant of Example 12 was also in the range of 0.5 - 2 mm, and the length range was 2 - 4 cm, which also conformed to the size range of conventional subcutaneous implants.

[0094] In another group of non - restrictive embodiments of the present invention, the active ingredients of the subcutaneous implant include chlorotriarylethylene and daidzein, and the mass ratio of chlorotriarylethylene to daidzein is 1:3 - 1:5. Weigh 10 mg of chlorotriarylethylene and 40 mg of daidzein. The outer shell is composed of chlorotriarylethylene and PLGA (LA:GA = 60:40), and the mass percentage ratio of chlorotriarylethylene to PLGA is 50:50. Weigh 10 mg of PLGA; regarding the molecular weight of PLGA, the mass percentage ratio of the polymer with an average molecular weight of 80,000 daltons is about 90%, and the mass percentage ratio of the polymer with an average molecular weight of 5000 daltons or less is about 10%. The inner core is composed of daidzein and PLGA (LA:GA = 50:50), and the mass percentage ratio of daidzein to PLGA is 50:50. Weigh 40 mg of PLGA; regarding the molecular weight of PLGA, the mass percentage ratio of the polymer with an average molecular weight of 60,000 daltons is about 85%, and the mass percentage ratio of the polymer with an average molecular weight of 5000 daltons or less is about 15%.

[0095] Example 13 was prepared using the same preparation method as in Example 1.

[0096] The diameter range of the subcutaneous implant of Example 13 was also in the range of 0.5 - 2 mm, and the length range was 2 - 4 cm, which also conformed to the size range of conventional subcutaneous implants.

[0097] In the comparative experiment method of the present invention, the components of the subcutaneous implant in Comparative Example 1 are the same as those in Example 1, except that the preparation methods are different. The specific steps are as follows: Estradiol valerate, genistein, PLGA (LA:GA = 60:40, wherein the mass percentage content ratio of the polymer with an average molecular weight of 80,000 Daltons is about 90%, and the mass percentage content ratio of the polymer with an average molecular weight of 5000 Daltons or less is about 10%) and PLGA (LA:GA = 50:50, wherein the mass percentage content ratio of the polymer with an average molecular weight of 60,000 Daltons is about 85%, and the mass percentage content ratio of the polymer with an average molecular weight of 5000 Daltons or less is about 15%) are respectively passed through a 100-mesh sieve three times for standby; then the barrel of the plunger extruder is heated to 80 °C; subsequently, 5 mg of estradiol valerate, 20 mg of genistein, 6.1 mg of PLGA (LA:GA = 60:40) and 24.4 mg of PLGA (LA:GA = 50:50) are mixed evenly and then put into the hopper and compacted and extruded. The extrusion speed is 3 mm / min and the pressure is 500 Mpa.

[0098] The diameter range of the subcutaneous implant in Comparative Example 1 is 1-2 mm, and the length range is 2-4 cm, which conforms to the size range of conventional subcutaneous implants.

[0099] At the same time, oral tablets containing 10 mg of estradiol valerate and 40 mg of genistein are prepared as Comparative Example 2.

[0100] Experimental example: In vitro release of subcutaneous implants

[0101] The samples prepared in Examples 1-13 and Comparative Examples 1-2 are respectively placed in centrifuge tubes, and each centrifuge tube is filled with 5 ml of PBS solution with a pH of 7.4. The centrifuge tubes are placed in a thermostatic air bath shaker, the temperature is set to (37 ± 0.5) °C, and the rotation speed is 100 rpm. Sampling is carried out at 1 h, 4 h, 10 h, 24 h, 2 days, 3 days, 5 days, 10 days, 15 days, and 30 days. Each time, 1 mL of sample is taken, and at the same time, PBS solution with the same volume and the same temperature is supplemented. The drug amount is measured, and the release rate and cumulative release degree are calculated.

[0102] The in vitro release rate results of Example 1 are as Figure 1 shown, and the cumulative release degree results are as Figure 2 shown. Since the in vitro implant is put into water, the outer shell starts to release. After the initial burst release, starting from the 3rd day, the release rate of the outer shell slowly decreases until the release is completed on the 30th day. The release of the inner core starts on the 5th day and reaches the peak release rate. After that, the release rate starts to slow down until the release is completed on the 30th day. Taking Examples 2-5 as an example, their shell-core cumulative release degrees are as Figures 3 to 6As shown, the outer shell starts to release as soon as it enters the water. The release rate of the outer shell begins to decline around 2 - 3 days. The cumulative release degree of the outer shell is about 90% on the 15th day, and the release rate further decreases until the release is completed on the 30th day. The release of the inner core starts on the 3rd - 5th day, and the release rate first increases and then decreases until the release is completed on the 30th day. The in vitro release results of Examples 6 - 13 are similar to those of Examples 1 - 5.

[0103] The cumulative release degrees of estradiol valerate and genistein in Comparative Example 1 are shown in Table 5. The cumulative release degree of the tablet drug in Comparative Example 2 is as Figure 7 shown.

[0104] Table 5: Cumulative Release Degree of the Drug in Comparative Example 1 (%)

[0105]

[0106]

[0107] Judging from the data in the figure, in Comparative Example 1, estradiol valerate and genistein start to release as soon as they enter the water, and the entire release curves almost completely overlap. In Comparative Example 2, it starts to release as soon as it enters the water, and the release rate is very fast, and the release is completed within 12 hours.

[0108] The technical features of the above-described embodiments can be combined arbitrarily. For the sake of brevity of description, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, it should be considered as within the scope described in this specification.

[0109] The above-described embodiments only represent several implementation manners of the present invention. Their descriptions are relatively specific and detailed, but they should not be construed as limiting the scope of the invention patent. It should be noted that for those of ordinary skill in the art, without departing from the concept of the present invention, several modifications and improvements can still be made, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the invention patent should be subject to the appended claims.

Claims

1. A subcutaneous implant, characterized in that, It includes a shell and a core. The shell wraps around the outside of the core and is in a columnar structure as a whole. The shell includes estrogen and a biodegradable polymer, and the core includes an estrogen receptor inhibitor and a biodegradable polymer. The mass ratio of the estrogen to the estrogen receptor inhibitor is 1:3 to 1:

6. The biodegradable polymer is a lactide-glycolide copolymer. In the shell, the mass percentage ratio of lactide to glycolide in the lactide-glycolide copolymer is 60:

40. The mass percentage ratio of the polymer with an average molecular weight of 80,000 Daltons in the lactide-glycolide copolymer is 90%, and the mass percentage ratio of the polymer with an average molecular weight of 5,000 Daltons or less in the lactide-glycolide copolymer is 10%. In the core, the mass percentage ratio of lactide to glycolide in the lactide-glycolide copolymer is 50:

50. The mass percentage ratio of the polymer with an average molecular weight of 60,000 Daltons in the lactide-glycolide copolymer is 85%, and the mass percentage ratio of the polymer with an average molecular weight of 5,000 Daltons or less in the lactide-glycolide copolymer is 15%.

2. The subcutaneous implant according to claim 1, wherein, The estrogen includes one or more of estradiol, estrone, estriol, ethinylestradiol, estradiol valerate, estradiol benzoate, quinestrol, ethinylestradiol 3-methyl ether, conjugated estrogens, nilestriol, diethylstilbestrol, hexestrol, and chlorotrianisene.

3. The subcutaneous implant according to claim 1, wherein, The estrogen receptor inhibitor includes a selective estrogen receptor downregulator and a selective estrogen receptor modulator. The selective estrogen receptor downregulator includes one or more of fulvestrant and AZD9496. The selective estrogen receptor modulator includes one or more of tamoxifen, raloxifene, lasofoxifene, and phytoestrogens.

4. The subcutaneous implant according to claim 3, wherein The phytoestrogen includes one or more of coumestrol, genistein, daidzein, and isoflavone.

5. The subcutaneous implant according to claim 1, characterized in that, The lactide-glycolide copolymer is a mixture of an uncapped and a capped lactide-glycolide copolymer, and the mass percentage ratio of the uncapped copolymer to the capped copolymer is 1:3 to 5:

1.

6. A preparation method of the subcutaneous implant according to claim 1, characterized in that The estrogen, the estrogen receptor inhibitor, and the biodegradable polymer are each passed through a 100-mesh sieve and reserved for use. Heat the barrel of the plunger extruder. Mix the estrogen and the biodegradable polymer evenly and put them into hopper one for compaction. Mix the estrogen receptor inhibitor and the biodegradable polymer evenly and put them into hopper two for compaction. The two hoppers are extruded simultaneously.

7. The preparation method according to claim 6, characterized in that, The extrusion speed is 2 - 4 mm / min, and the pressure is 400 - 600 Mpa.

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