Androgen-containing subcutaneous implant and its preparation method

Abstract

The present invention relates to a subcutaneous implant for hormone replacement therapy, which comprises a shell and a core. The shell wraps around the outside of the core and has an overall columnar structure. The shell comprises an androgen and a biodegradable polymer, and the core comprises an enzyme inhibitor and a biodegradable polymer. The enzyme inhibitor comprises a 5-α reductase inhibitor and an aromatase inhibitor. When implanted into the body, the androgen in the shell continuously releases a fixed amount of drug stably every day. As the drug in the shell dissolves and diffuses and the material degrades, the active drug in the core gradually releases slowly 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] Male androgen deficiency refers to a disease in which certain parts of the hypothalamic-pituitary-gonadal axis are diseased and cannot produce normal physiological levels of androgens. Its causes can be divided into primary androgen deficiency (testicular insufficiency), secondary androgen deficiency (hypothalamic-pituitary insufficiency), and partial androgen deficiency in middle-aged and elderly men (male menopause). According to WHO statistics, more than 400 million men worldwide are suffering from androgen deficiency problems. Approximately 39% of men over 40 years old have androgen deficiency problems, and their testosterone levels decline at a rate of 1% - 2% per year.

[0003] Lower-than-normal levels of androgens can bring about a series of physiological and pathological changes: (1) In terms of sexual symptoms, it often manifests as incomplete development of secondary sexual characteristics, eunuchoidism, azoospermia, low libido, poor sexual ability, erectile dysfunction, etc.; (2) In terms of psychological symptoms, it often manifests as depression, irritability, nervousness, sleep disorders, inattention, low memory, etc.; (3) In terms of physical symptoms, it often manifests as atrophy of target organs (such as smaller testicular volume, loss of axillary and pubic hair), decreased bone density, reduced skeletal muscle volume and strength, increased visceral fat mass, and increased body mass index. This increases the probability of male androgen deficiency patients suffering from cardiovascular diseases, type II diabetes, osteoporosis, endocrine diseases, prostate diseases, etc., seriously affecting the quality of life.

[0004] For such patients, clinically, the main treatment option is hormone replacement therapy, that is, a treatment method for treating diseases caused by decreased or lacking hormone secretion by supplementing hormones to relieve health problems related to the lack of androgens. Common administration methods of hormone therapy are divided into oral route, intramuscular injection route, transdermal route (such as oral mucosal preparations, dosage forms such as gels, ointments, scrotal and non-scrotal patches), and subcutaneous implantation route.

[0005] Oral preparations have the longest duration and the widest range, but have the following disadvantages: (1) High frequency of taking medicine, low patient compliance. (2) Frequent administration is required, and the drug concentration in serum fluctuates greatly. (3) Some oral preparations have hepatotoxicity, such as fluoxymesterone and methyltestosterone.

[0006] The intramuscular injection route can avoid the first-pass effect of the liver, but some injections such as testosterone injections can produce a non-physiological serum testosterone level, reaching a peak rapidly after injection and then gradually decreasing within two weeks.

[0007] The transdermal route has the following disadvantages: (1) Oral mucosal preparations such as testosterone buccal tablets are applied at the junction of the gum and the upper lip and release continuously in the oral cavity for 12 hours. They are absorbed through the oral mucosa into the blood and then directly transported to the superior vena cava, but they can cause taste changes in patients and stimulate the gums. (2) Gels and ointments need to be used frequently, and the dosage and the skin area of application are not standardized. It is difficult for patients to control the dosage, and they may get on partners or children, posing a threat to the health of others. (3) Patches have been continuously optimized on this basis, with a reduced dosing frequency and relatively stable drug release. However, 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 over time.

[0008] The subcutaneous implantation route can provide relatively lower and more stable serum androgen levels, and the dosing cycle is relatively long. However, continuous androgen release will bring some obvious side effects. For example, 5-α reductase in the human body can convert absorbed testosterone in the body into dihydrotestosterone (DHT). DHT is a more potent androgen than testosterone, and the effect of testosterone is amplified in tissues that produce DHT, which can easily lead to prostate hyperplasia or even prostate cancer. Aromatase in men can convert some androgens into estrogen, leading to gynecomastia in men, and through negative feedback, the gonadotropin level is too low, which may temporarily inhibit testicular spermatogenesis, resulting in azoospermia or severe oligospermia. At the same time, some studies have shown that it will increase the risk of coronary heart disease. Therefore, there is a need for a dosing method that can continuously administer drugs with relatively fewer side effects in clinical practice. Summary of the Invention

[0009] One aspect of the present invention is to provide a subcutaneous implant that can continuously supplement androgens with relatively fewer side effects.

[0010] The subcutaneous implant of the present application has an overall columnar structure; it includes an outer shell and an inner core. The outer shell includes an androgen and a biodegradable polymer, and the inner core includes an enzyme inhibitor and a biodegradable polymer. Specifically, the enzyme inhibitor includes a 5-α reductase inhibitor and an aromatase inhibitor.

[0011] Androgens include natural androgens and synthetic androgens. Natural androgens include testosterone, androstenedione, and dehydroepiandrosterone; synthetic androgens include methyltestosterone, testosterone propionate, testosterone enanthate, and testosterone undecanoate. The androgens of the present application are selected from one or more of them.

[0012] 5-α reductase inhibitors can be divided into natural 5-α reductase inhibitors, synthetic steroidal 5-α reductase inhibitors, and synthetic non-steroidal 5-α reductase inhibitors. Among them, natural 5-α reductase inhibitors include extracts of Serenoa repens, Myristica fragrans, Nymphaea odorata, Camellia oleifera Abel. fruit husk, Cicer arietinum, Plantago asiatica, Pterocarpus indicus, Nelumbo nucifera Gaertn. plumule, Rapeseed pollen, Ganoderma lucidum, Pueraria lobata, Polygonum multiflorum, and Panax ginseng, etc. Synthetic steroidal 5-α reductase inhibitors include finasteride, dutasteride, and epristeride, etc. Synthetic non-steroidal 5-α reductase inhibitors include epristeride, etc. The 5-α reductase inhibitor of the present application is selected from one or more of them.

[0013] Aromatase inhibitors can be divided into natural aromatase inhibitors, synthetic steroidal aromatase inhibitors, and synthetic non-steroidal aromatase inhibitors. Among them, natural aromatase inhibitors include flavonoid compounds such as flavone, isoflavone, dihydroflavone, and chrysin, etc., chromone and xanthone compounds, coumarin compounds, sesquiterpene lactones, resveratrol, lignans, etc. Synthetic steroidal aromatase inhibitors include testolactone, formestane, and exemestane, etc. Synthetic non-steroidal aromatase inhibitors include aminoglutethimide, anastrozole, and letrozole, etc. The aromatase inhibitor of the present application is selected from one or more of them.

[0014] In some embodiments, the mass ratio of androgen to 5-α reductase inhibitor is 5:1 to 20:1;

[0015] Alternatively, the mass ratio of androgen to aromatase inhibitor is 40:1 to 80:1.

[0016] The degradable polymer includes polylactic-co-glycolic acid (PLGA), specifically a mixture of end-capped PLGA polymers.

[0017] In some embodiments, the PLGA of the outer shell is a mixture of ester-capped and carboxyl-capped PLGA polymers, wherein the mass ratio of the ester-capped PLGA polymer to the carboxyl-capped PLGA polymer is 1:10 to 10:1, and the PLGA of the inner core is a carboxyl-capped PLGA polymer.

[0018] In some embodiments, the mass percentage ratio of lactic acid (LA) to glycolic acid (GA) in the outer shell PLGA is 75:25, and the mass percentage ratio of lactic acid (LA) to glycolic acid (GA) in the inner core PLGA is 50:50.

[0019] The mass percentage ratio of androgen to PLGA in the outer shell is 60:40, and the mass percentage ratio of the enzyme inhibitor to PLGA in the inner core is 65:35.

[0020] In some embodiments, the subcutaneous implant further includes a release enhancer.

[0021] Optionally, the release enhancer includes one or more of hydroxypropyl cellulose, polyethylene glycol, and poloxamer.

[0022] Another aspect of the present invention also provides a method for preparing a subcutaneous implant:

[0023] First, the androgen, enzyme inhibitor, and degradable polymer are respectively sieved through an 80-200 mesh sieve for standby. Specifically, the enzyme inhibitor includes a 5-α reductase inhibitor and an aromatase inhibitor;

[0024] Secondly, heat the barrel of the plunger extruder;

[0025] Then, the androgen and the degradable polymer are mixed evenly and put into hopper one for compaction, and the enzyme inhibitor and the degradable polymer are mixed evenly and put into hopper two for compaction;

[0026] 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.

[0027] Optionally, the extrusion speed is 2-4 mm / min and the pressure is 400-500 Mpa.

[0028] Furthermore, the barrel of the plunger extruder is heated to 80 °C. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] 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 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, without creative efforts, other drawings can also be obtained based on these drawings.

[0030] Figure 1 It is the graph of the cumulative release degree of the nucleus accumbens in Example 1 of the present invention,

[0031] Figure 2 It is the graph of the cumulative release degree of the nucleus accumbens in Example 2 of the present invention;

[0032] Figure 3 It is the graph of the cumulative release degree of the nucleus accumbens in Example 3 of the present invention;

[0033] Figure 4 It is the graph of the cumulative release degree of the nucleus accumbens in Example 4 of the present invention;

[0034] Figure 5 It is the graph of the cumulative release degree of the nucleus accumbens in Comparative Example 1 of the present invention;

[0035] Figure 6 It is the graph of the cumulative release degree of testosterone undecanoate and chrysin in Comparative Example 2 of the present invention;

[0036] Figure 7 This is the cumulative release rate graph of testosterone undecanoate and chrysin in Comparative Example 3 of the present invention. Detailed implementation manners

[0037] 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 described or illustrated as part of one embodiment can be used in another embodiment to yield a still further embodiment.

[0038] 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.

[0039] 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 including the listed features.

[0040] In the present invention, regarding numerical ranges, unless otherwise specified, the above numerical ranges are considered continuous and include the minimum and maximum values 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.

[0041] In this article, regarding the unit of a data range, if there is only a unit 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).

[0042] The present invention relates to a subcutaneous implant, which is integrally in a columnar structure 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 an androgen and a biodegradable polymer, and the core includes an enzyme inhibitor and a biodegradable polymer. Specifically, the enzyme inhibitor includes a 5-α reductase inhibitor and an aromatase inhibitor. Since the biodegradable polymer is a hydrophilic material, after contacting water, the shell starts to release the hormone contained therein first, and as time progresses, the core starts to release after contacting water slightly later, thereby realizing sequential administration of the two hormones.

[0043] Androgens are a class of hormones that promote the maturation of male reproductive organs, the development of secondary sexual characteristics, and maintain their normal functions. The present invention aims to treat diseases caused by reduced or deficient androgen secretion by supplementing androgens through hormone replacement therapy. Androgens can be classified into natural androgens and synthetic androgens.

[0044] Natural androgens include testosterone, androstenedione, dehydroepiandrosterone, etc.

[0045] Synthetic androgens include methyltestosterone, testosterone propionate, testosterone enanthate, testosterone undecanoate, etc.

[0046] Currently, the commonly used androgen is testosterone. Considering that 5-α reductase in the body can convert continuously released testosterone into dihydrotestosterone (DHT), which is a more potent androgen than testosterone, and the effect of testosterone is amplified in tissues that produce DHT, it may increase the risk of prostate hyperplasia and prostate cancer. 5-α reductase inhibitors, by inhibiting the activity of 5-α reductase and reducing the production of DHT, are effective means for treating androgen-dependent diseases and can be classified into natural 5-α reductase inhibitors and synthetic 5-α reductase inhibitors.

[0047] Natural 5-α reductase inhibitors include extracts of saw palmetto, nutmeg, perfume lotus, tea-oil camellia fruit, chickpea, plantain seed, red sandalwood, lotus plumule, rape pollen, ganoderma lucidum, kudzu flower, fleeceflower root, and red ginseng, etc.

[0048] Synthetic 5-α reductase inhibitors include two categories: steroidal and non-steroidal. Steroidal 5-α reductase inhibitors include finasteride, dutasteride, epristeride, etc. Non-steroidal 5-α reductase inhibitors include epristeride, etc.

[0049] Aromatase is the product of the CYP-19 gene of the cytochrome P450 superfamily, which can catalyze the conversion of peripheral androgens into estrogens, leading to gynecomastia in men, inhibiting testicular spermatogenic function, and simultaneously posing a risk of coronary heart disease. Aromatase inhibitors can inhibit aromatase and reduce plasma estrogen levels to achieve the effect of inhibiting the growth of breast tumor cells. Aromatase inhibitors can be classified into natural aromatase inhibitors and synthetic aromatase inhibitors.

[0050] Natural aromatase inhibitors include flavonoids (such as flavone, isoflavone, dihydroflavone, and chrysin, etc.), chromone and xanthone compounds, coumarin compounds, sesquiterpene lactones, resveratrol, lignans, etc.

[0051] Synthetic aromatase inhibitors include two categories: steroidal and non-steroidal. Steroidal aromatase inhibitors include testolactone, formestane, exemestane, etc. Non-steroidal aromatase inhibitors include aminoglutethimide, anastrozole, letrozole, etc.

[0052] Optionally, the mass ratio of androgen to 5-α reductase inhibitor is 5:1 to 20:1.

[0053] Optionally, the mass ratio of androgen to aromatase inhibitor is 40:1 to 80:1.

[0054] Too little 5-α reductase inhibitor or aromatase inhibitor is not enough to achieve the desired effect of reducing DHT or estrogen production, while too much 5-α reductase inhibitor or aromatase inhibitor will also affect the normal operation of the human body's metabolic mechanism.

[0055] 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 adherence, and has high patient compliance. The biodegradable polymer includes polylactide-glycolide copolymer (PLGA), which is polymerized from lactide (LA) and glycolide (GA). By adjusting the ratio of LA and GA, the hydrophilicity and degradation rate of PLGA can be adjusted. At the same time, PLGA is a mixture of ester-capped and carboxyl-capped. The terminal carboxyl group in the PLGA chain is more hydrophilic and there is an autocatalytic degradation process. Therefore, the carboxyl-capped PLGA polymer degrades faster in water, and the capping in the chain prolongs the degradation time. Therefore, the hydrophilicity and degradation rate of PLGA can also be adjusted by adjusting the ratio of ester-capped and carboxyl-capped PLGA polymers.

[0056] As used herein, "ester-capped polymer" or "ester-capped copolymer" means that the end group of the polymer or copolymer is an ester bond. The ester-capped copolymer has a lower polarity, poor hydrophilicity, and a longer degradation time.

[0057] As used herein, "carboxyl-capped polymer" or "carboxyl-capped copolymer" means that the end group of the polymer or copolymer is a carboxyl group. The carboxyl-capped copolymer has a higher polarity, stronger hydrophilicity, and a shorter degradation time.

[0058] Optionally, in the present invention, the mass percentage ratio of LA and GA is 50:50 to 75:25; the mass ratio of ester-capped and carboxyl-capped PLGA polymers is 1:10 to 10:1; the administration cycle is 180 days.

[0059] Preferably, the mass percentage ratio of LA and GA in the outer shell is 75:25, and the mass percentage ratio of LA and GA in the inner core is 50:50.

[0060] In some embodiments, the subcutaneous implant further includes a release enhancer, and the release enhancer includes one or more of hydroxypropyl cellulose, polyethylene glycol, and poloxamer.

[0061] Each implant is equipped with an independent sterilized pre-filled 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 six months. Since the shell is implanted into the body, a fixed amount of drug is continuously and stably released daily from the androgen. As the drug in the shell part 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.

[0062] Another aspect of the present invention also provides a preparation method for subcutaneous implants:

[0063] First, the androgen, enzyme inhibitor, and degradable polymer are each passed through an 80-200 mesh sieve three times for standby. Specifically, the enzyme inhibitor includes a 5-α reductase inhibitor and an aromatase inhibitor;

[0064] Second, heat the barrel of the plunger extruder to 80 °C;

[0065] Then, mix the androgen and the degradable polymer evenly and put them into hopper one for compaction. Mix the enzyme inhibitor and the degradable polymer evenly and put them into hopper two for compaction;

[0066] 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.

[0067] Optionally, the extrusion speed is 3 mm / min, and the pressure is 400-500 Mpa.

[0068] 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 drug administration. In the form of subcutaneous implants, the blood drug concentration in the patient's body can be maintained relatively stable, improving the safety of medication and avoiding problems such as patients forgetting to take medicine or taking the wrong dose.

[0069] Next, the embodiments of the present invention will be described in detail in conjunction with examples.

[0070] In a non-limiting embodiment of the present invention, the subcutaneous implant includes a shell and a core, and the active ingredients include testosterone undecanoate and chrysin. The mass ratio of testosterone undecanoate to chrysin is 40:1 to 80:1.

[0071] The outer shell is composed of testosterone undecanoate and the biodegradable polymer PLGA, where the mass percentage ratio of testosterone undecanoate to PLGA is 60:40. The mass percentage ratio of lactide (LA) to glycolide (GA) in PLGA is LA:GA = 75:25. PLGA is a mixture of ester-capped PLGA polymer and carboxyl-capped PLGA polymer, and the mass ratio range of the ester-capped PLGA polymer to the carboxyl-capped PLGA polymer is 1:10 to 10:1.

[0072] The core is composed of chrysin and the biodegradable polymer PLGA. The mass percentage ratio of chrysin to PLGA in the core is 65:35. The mass percentage ratio of lactide (LA) to glycolide (GA) in PLGA is LA:GA = 50:50, and PLGA is all carboxyl-capped PLGA polymer.

[0073] The specific content of each component is shown in Table 1 below:

[0074] Table 1: The shell-core components and their contents of Examples 1 to 4

[0075]

[0076] Subcutaneous implants were prepared according to the groups in the above table. Taking Example 1 as an example, the active ingredient testosterone undecanoate, PLGA (LA:GA = 75:25), chrysin, and PLGA (LA:GA = 50:50) were each passed through a 200-mesh sieve three times for standby. Then, the barrel of the plunger extruder was heated to 80 °C. 10 mg of testosterone undecanoate was taken and mixed evenly with 6.667 mg of PLGA (LA:GA = 75:25), and then transferred to Hopper 1 and compacted; 0.25 mg of chrysin was taken and mixed evenly with 0.135 mg of PLGA (LA:GA = 50:50), and then transferred to Hopper 2 and compacted. Then, the mixtures in the two hoppers were simultaneously extruded at an extrusion speed of 3 mm / min and an extrusion pressure of 450 Mpa. The extrudate obtained was a columnar structure, more specifically a rod-like structure or a cylindrical structure.

[0077] The testosterone undecanoate content of the extrudate was tested by liquid chromatography. According to the required testosterone undecanoate content of a single implant according to the experimental design, the mass of the subcutaneous implant could be calculated. Based on this, the diameter and length of the subcutaneous implant were determined.

[0078] Examples 2 to 4 were prepared respectively by the same preparation method as Example 1, and the parameters of the subcutaneous implants are shown in Table 2 below.

[0079] Table 2: Related parameters of the implants prepared in Examples 1 to 4

[0080] Example Diameter (mm) Length (cm) 1 1.80 4.00 2 2.00 3.90 3 2.00 3.85 4 2.00 4.00

[0081] As can be seen from Table 2, the diameter range of the subcutaneous implants in Examples 1 to 4 is 1.8 to 2 mm, and the length range is 3.85 to 4 cm, which conforms to the size range of conventional subcutaneous implants, i.e., the diameter range of 0.5 to 2 mm and the length range of 2 to 4 cm.

[0082] In another group of non-limiting embodiments of the present invention, the active ingredients of the subcutaneous implant include testosterone enanthate and saw palmetto extract, and the mass ratio of testosterone enanthate to saw palmetto extract is 5:1 to 20:1. The outer shell is composed of testosterone enanthate and PLGA, and the mass percentage ratio of testosterone enanthate to PLGA is 60:40. The mass percentage ratio of lactide (LA) to glycolide (GA) in PLGA is LA:GA = 75:25, and PLGA is a mixture of ester-capped PLGA polymer and carboxyl-capped PLGA polymer, and the mass ratio range of the ester-capped PLGA polymer to the carboxyl-capped PLGA polymer is 1:10 to 10:1.

[0083] The inner core is composed of saw palmetto extract and the biodegradable polymer PLGA, and the mass percentage ratio of saw palmetto extract to PLGA in the inner core is 65:35. The mass percentage ratio of lactide (LA) to glycolide (GA) in PLGA is LA:GA = 50:50, and PLGA is all carboxyl-capped PLGA polymer.

[0084] Using the same preparation method as in Example 1 and using the components and masses shown in Table 3 below, Examples 5 to 6 were prepared.

[0085] Table 3: Shell-core components and their contents of Examples 5 to 6

[0086]

[0087] The diameter range of the subcutaneous implants in Examples 5 to 6 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.

[0088] In another group of non-limiting embodiments of the present invention, the active ingredients of the subcutaneous implant include testosterone undecanoate and epristeride, and the mass ratio of testosterone undecanoate to epristeride is 10:1 to 30:1. The outer shell is composed of testosterone undecanoate and PLGA, and the mass percentage ratio of testosterone undecanoate to PLGA is 60:40. The mass percentage ratio of lactide (LA) to glycolide (GA) in PLGA is LA:GA = 75:25, and PLGA is a mixture of ester-capped PLGA polymer and carboxyl-capped PLGA polymer, and the mass ratio range of the ester-capped PLGA polymer to the carboxyl-capped PLGA polymer is 1:10 to 10:1.

[0089] The core consists of epristeride and the biodegradable polymer PLGA. The mass percentage ratio of epristeride to PLGA in the core is 65:35. The mass percentage ratio of lactide (LA) to glycolide (GA) in PLGA is LA:GA = 50:50, and all of the PLGA is carboxyl-terminated PLGA polymer.

[0090] Using the same preparation method as in Example 1 and the components and masses shown in Table 4 below, Examples 7 - 8 were prepared.

[0091] Table 4: The shell-core components and their contents of Examples 7 - 8

[0092]

[0093]

[0094] The diameter range of the subcutaneous implants of Examples 7 - 8 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.

[0095] In another group of non-limiting embodiments of the present invention, the active ingredients of the subcutaneous implant include androstenedione and finasteride. Weigh 10 mg of androstenedione and 0.667 mg of finasteride. The outer shell consists of androstenedione and PLGA (LA:GA = 75:25). The mass percentage ratio of androstenedione to PLGA is 60:40. The PLGA is a mixture of ester-terminated PLGA polymer and carboxyl-terminated PLGA polymer. Weigh 5.556 mg of ester-terminated PLGA and 1.111 mg of carboxyl-terminated PLGA polymer.

[0096] The core consists of finasteride and the biodegradable polymer PLGA (LA:GA = 50:50, carboxyl-terminated). The mass percentage ratio of finasteride to PLGA in the core is 65:35. Weigh 0.359 mg of PLGA.

[0097] Using the same preparation method as in Example 1, Example 9 was prepared.

[0098] The diameter range of the subcutaneous implant of Example 9 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.

[0099] In another group of non-limiting embodiments of the present invention, the active ingredients of the subcutaneous implant include dehydroepiandrosterone and testolactone. Weigh 10 mg of dehydroepiandrosterone and 0.5 mg of testolactone. The outer shell is composed of dehydroepiandrosterone and PLGA (LA:GA = 75:25). The mass percentage ratio of dehydroepiandrosterone to PLGA is 60:40. PLGA is a mixture of an ester-capped PLGA polymer and a carboxyl-capped PLGA polymer. Weigh 5.556 mg of the ester-capped PLGA polymer and 1.111 mg of the carboxyl-capped PLGA polymer.

[0100] The inner core is composed of testolactone and a degradable polymer PLGA (LA:GA = 50:50, carboxyl-capped). The mass percentage ratio of testolactone to PLGA in the inner core is 65:35. Weigh 0.269 mg of PLGA.

[0101] Using the same preparation method as in Example 1, Example 10 is prepared.

[0102] The diameter range of the subcutaneous implant of Example 10 is also in the range of 0.5 - 2 mm, and the length range is 2 - 4 cm, which also conforms to the size range of conventional subcutaneous implants.

[0103] In another group of non-limiting embodiments of the present invention, the active ingredients of the subcutaneous implant include methyltestosterone and aminoglutethimide. Weigh 10 mg of methyltestosterone and 0.33 mg of aminoglutethimide. The outer shell is composed of methyltestosterone and PLGA (LA:GA = 75:25). The mass percentage ratio of methyltestosterone to PLGA is 60:40. PLGA is a mixture of an ester-capped PLGA polymer and a carboxyl-capped PLGA polymer. Weigh 5.556 mg of the ester-capped PLGA polymer and 1.111 mg of the carboxyl-capped PLGA polymer.

[0104] The inner core is composed of aminoglutethimide and a degradable polymer PLGA (LA:GA = 50:50, carboxyl-capped). The mass percentage ratio of aminoglutethimide to PLGA in the inner core is 65:35. Weigh 0.178 mg of PLGA.

[0105] Using the same preparation method as in Example 1, Example 11 is prepared.

[0106] The diameter range of the subcutaneous implant of Example 11 is also in the range of 0.5 - 2 mm, and the length range is 2 - 4 cm, which also conforms to the size range of conventional subcutaneous implants.

[0107] In the comparative experiment mode of the present invention, using the same method as in Example 1, Comparative Example 1 with 10 mg of testosterone undecanoate and 1 mg of chrysin as the active ingredients is prepared, and the other components are the same as those in Example 1.

[0108] The components of the subcutaneous implant in Comparative Example 2 were the same as those in Example 1, except that the preparation method was different. The specific steps were as follows: Testosterone undecanoate, chrysin, PLGA (LA:GA = 75:25, ester group terminated: carboxyl group terminated = 10:1), and PLGA (LA:GA = 50:50, carboxyl group terminated) were each passed through a 100-mesh sieve three times and set aside. Then, the barrel of the plunger extruder was heated to 80 °C. Subsequently, 10 mg of testosterone undecanoate, 0.25 mg of chrysin, 6.667 mg of PLGA (LA:GA = 75:25), and 0.135 mg of PLGA (LA:GA = 50:50) were mixed evenly and then placed in the hopper and compacted and extruded. The extrusion speed was 3 mm / min, and the pressure was 450 Mpa.

[0109] The diameter range of the subcutaneous implant in Comparative Example 2 was also 0.5 - 2 mm, and the length range was 2 - 4 cm, which also met the size range of conventional subcutaneous implants.

[0110] Oral tablets containing 10 mg of testosterone undecanoate and 0.25 mg of chrysin were prepared as Comparative Example 3. Experimental Example 1: In vitro release of subcutaneous implants

[0111] The samples were prepared according to the methods in Examples 1 - 11 and Comparative Examples 1 - 3.

[0112] The samples were placed in centrifuge tubes respectively, and each centrifuge tube was filled with 5 ml of PBS solution with a pH of 7.4. The centrifuge tubes were placed in a constant temperature air bath shaker, the temperature was set at (37 ± 0.5) °C, and the rotation speed was 100 rpm. Sampling was carried out every 0.04, 0.5, 3, 10, 15, 35, 50, 80, 90, 100, 130, 150, 165, 170, 180 days. Each time, 1 mL of sample was taken, and at the same time, PBS solution of the same volume and the same temperature was replenished. The drug content was measured, and the cumulative release rate was calculated. Taking Examples 1 - 4 as an example, the cumulative release rate of their core-shell is shown in Table 5. The cumulative release rates of testosterone undecanoate and chrysin in Comparative Examples 1 - 3 are shown in Table 6.

[0113] Table 5: Cumulative release rate of core-shell in Examples 1 - 4 (%)

[0114]

[0115]

[0116] Table 6: Cumulative release rate of testosterone undecanoate and chrysin in Comparative Examples 1 - 3 (%)

[0117]

[0118]

[0119] According to the experimental results, cumulative release curves of androgen (shell) and 5-α reductase inhibitor / aromatase inhibitor (core) over time were plotted respectively.

[0120] Taking Examples 1 to 4 as examples, their shell-core cumulative release degrees are as Figures 1 - 4 shown. Since the autologous implant was placed in water, the outer shells of all examples started to release. Chrysin in Example 1 started to release on the 3rd day. The release rate of testosterone undecanoate core was relatively fast from the 15th to the 100th day, and the release rate of chrysin core slowed down from the 100th to the 180th day, and finally the shell-core release was completed around 180 days. The release pattern of chrysin in Example 2 was consistent with that in Example 1, and the release rate of testosterone undecanoate from the 0th to the 100th day was faster than that in Example 1, presumably due to a higher proportion of carboxyl-terminated groups in the outer shell. The release pattern of Example 3 was consistent with that of Example 1, and the release pattern of Example 4 was consistent with that of Example 2. For Examples 5 to 11, the outer shell started to release first, and finally the outer shell and the inner core completed the release around 180 days.

[0121] The release results of Comparative Examples 1 to 3 are as Figures 5 - 6 shown. Judging from the data in the figure, the release pattern of Comparative Example 1 was similar to that of Example 1, and the release rate of chrysin in the core was slightly faster than that in Example 1. In Comparative Example 2, both testosterone undecanoate and chrysin started to release simultaneously from the moment of entering water, and the entire release curve almost completely overlapped. Comparative Example 3 started to release when entering water, and the release rate was very fast, and the release was completed within 12 hours.

[0122] 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 the scope recorded in this specification.

[0123] The above-described embodiments merely represent several implementation manners of the present invention, and their descriptions are relatively specific and detailed, but 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 an androgen and a biodegradable polymer, and the core includes an enzyme inhibitor and a biodegradable polymer. The enzyme inhibitor includes a 5-α reductase inhibitor and an aromatase inhibitor; The biodegradable polymer includes a lactide-glycolide copolymer; The mass percentage ratio of the androgen to the lactide-glycolide copolymer in the shell is 60:40, and the mass percentage ratio of the enzyme inhibitor to the lactide-glycolide copolymer in the core is 65:35; The lactide-glycolide copolymer in the shell is a mixture of ester group-terminated and carboxyl group-terminated, and the mass percentage ratio of lactide-glycolide is 75:25, and the mass ratio of ester group-terminated to carboxyl group-terminated is 1:10 to 10:1; The lactide-glycolide copolymer in the core is a carboxyl group-terminated copolymer, and the mass percentage ratio of lactide-glycolide is 50:

50.

2. The subcutaneous implant according to claim 1, characterized in that, The androgen includes one or more of testosterone, androstenedione, dehydroepiandrosterone, methyltestosterone, testosterone propionate, testosterone enanthate, testosterone undecanoate; 3. The subcutaneous implant according to claim 1, characterized in that, The 5-α reductase inhibitor includes one or more of Serenoa repens extract, Myristica fragrans extract, Nymphaea odorata extract, Camellia oleifera Abel. extract, Cicer arietinum extract, Plantago asiatica extract, Pterocarpus indicus extract, Nelumbo nucifera Gaertn. extract, Brassica campestris pollen extract, Ganoderma lucidum extract, Pueraria lobata extract, Polygonum multiflorum extract, Panax ginseng extract, finasteride, dutasteride, epristeride, epristeride; 4. The subcutaneous implant according to claim 1, characterized in that, The aromatase inhibitors include flavones, isoflavones, dihydroflavones, chrysin 、 chromones, xanthones, coumarin compounds, sesquiterpene lactone compounds, resveratrol, lignans 、 testolactone, formestane, exemestane 、 aminoglutethimide, anastrozole, letrozole, or one or more of them.

5. The subcutaneous implant according to claim 1, characterized in that, The mass ratio of the androgen to the 5-α reductase inhibitor is 5:1 to 20:

1.

6. The subcutaneous implant according to claim 1, characterized in that, The mass ratio of the androgen to the aromatase inhibitor is 40:1 to 80:

1.

7. A preparation method of the subcutaneous implant according to claim 1, characterized in that, Pass the androgen enzyme inhibitor and the biodegradable polymer through a sieve of 80 to 200 meshes respectively for standby. The enzyme inhibitor includes a 5-α reductase inhibitor and an aromatase inhibitor; Heat the barrel of the plunger extruder; Mix the androgen and the biodegradable polymer evenly and put them into hopper one for compaction, and mix the enzyme inhibitor and the biodegradable polymer evenly and put them into hopper two for compaction; the two hoppers are extruded simultaneously.

8. The preparation method according to claim 7, characterized in that, The extrusion speed is 2 to 4 mm / min, and the pressure is 400 to 500 Mpa.

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