Fully-degradable arterial embolism microspheres as well as preparation method and application thereof

Abstract

The invention provides a fully-degradable arterial embolism microsphere as well as a preparation method and application thereof. The preparation method comprises the following steps: adding the degradable polymer into an organic solvent to prepare an oil phase; adding an emulsifier into water to prepare a water phase; fully emulsifying the oil phase and the water phase to form an emulsion; under a negative pressure condition, stirring the emulsion to solidify the emulsion, filtering to obtain a solid, cleaning the solid, and carrying out low-temperature vacuum drying to obtain microspheres; weighing polysaccharide and a cross-linking agent, adding the polysaccharide and the cross-linking agent into water, stirring and dissolving to obtain a polysaccharide polymer solution; and adding the microspheres into a polysaccharide polymer solution, fully infiltrating, filtering, heating and drying in vacuum to obtain the crosslinked polysaccharide shell coated microspheres. The microspheres provided by the invention can be completely degraded and metabolized in vivo, the embolism degradation effect can be maintained for 12 months, and the microspheres can be used for blood supply of embolism of prostatic artery by a minimally invasive intervention technology after carrying drugs, and can improve and treat prostate related diseases.

Description

Technical Field

[0001] This invention belongs to the field of medical device technology, specifically relating to a fully degradable arterial embolization microsphere, its preparation method and application, especially for the preparation of drug-loaded microspheres for prostate-related diseases and for the treatment of prostate-related diseases. Background Technology

[0002] Benign prostatic hyperplasia (BPH) is one of the most common diseases among older men. Its prevalence increases with age, and it is the leading cause of lower urinary tract symptoms, affecting approximately one-quarter of men worldwide. Although BPH is not a fatal disease, its global burden is growing.

[0003] Currently, transurethral resection of the prostate (TURP) remains the gold standard for surgical treatment of benign prostatic hyperplasia (BPH). However, TURP requires general anesthesia and is a relatively invasive surgical procedure. Elderly patients often have coexisting heart, lung, or kidney dysfunction, and general anesthesia and invasive surgery significantly increase perioperative risks. In some cases, elderly patients are even ineligible for the procedure due to inadequate anesthesia assessment. Furthermore, the incidence of postoperative complications such as retrograde ejaculation, bleeding, and urinary tract infections remains relatively high.

[0004] In 2000, Demeritt et al. reported a case of hematuria caused by benign prostatic hyperplasia (BPH) treated with polyvinyl alcohol (PVA) particle embolization. The hematuria disappeared immediately after the procedure, and follow-up at 5 and 12 months showed that the patient's prostate volume had decreased by 52% and 62%, respectively, compared to the initial volume. Subsequently, researchers discovered that by embolizing arteries, reducing blood supply to the prostate tissue, and blocking local microcirculation, ischemia, necrosis, and absorption of the prostate parenchyma can occur, reducing prostate volume and thus alleviating obstructive symptoms. Furthermore, due to the reduced blood supply, the amount of androgens entering the prostate decreases, weakening their stimulation of prostate cell proliferation and slowing the progression of BPH. Simultaneously, the reduced blood supply to nerve tissue within the embolization area decreases nerve excitability and α-receptor excitability, leading to relaxation of prostate smooth muscle and improving bladder outlet obstruction. Currently, there are no fully degradable microspheres specifically for prostate arteries in clinical practice. The reported PVA microspheres for prostate embolization cannot be degraded or metabolized in vivo, posing a potential carcinogenic risk if retained long-term in the body. At the same time, if the surgeon is not familiar with vascular anatomy and accidentally embolizes blood vessels in other parts of the body, it can cause permanent ischemia in other organs (such as penile ischemia and perianal ischemia).

[0005] Therefore, there is an urgent need to provide a fully degradable arterial embolization microsphere for the preparation of drug-loaded microspheres for prostate-related diseases and for the treatment of prostate-related diseases. Summary of the Invention

[0006] Based on the deficiencies of existing technologies, the first objective of this invention is to provide a method for preparing fully degradable arterial embolization microspheres; the second objective of this invention is to provide a method for preparing fully degradable arterial embolization microspheres; the third objective of this invention is to provide a method for preparing fully degradable arterial embolization drug-loaded microspheres; the fourth objective of this invention is to provide fully degradable arterial embolization drug-loaded microspheres prepared by this method; the fifth objective of this invention is to provide the application of fully degradable arterial embolization drug-loaded microspheres in the preparation of drugs for treating prostate diseases; and the sixth objective of this invention is to provide a method for treating prostate diseases using fully degradable arterial embolization drug-loaded microspheres.

[0007] The objective of this invention is achieved through the following technical solution:

[0008] On the one hand, the present invention provides a method for preparing fully degradable arterial embolization microspheres, the method comprising the following steps:

[0009] Step 1: Weigh the biodegradable polymer and add it to an organic solvent and stir to dissolve, obtaining the oil phase; weigh the emulsifier and add it to water and heat and stir to dissolve, obtaining the aqueous phase; slowly add the oil phase to the aqueous phase, using a stirring method of high speed first and then low speed to fully emulsify the oil phase in the aqueous phase to form an emulsion;

[0010] Step 2: Under negative pressure, the emulsion is stirred to evaporate the organic solvent and solidify. The solid obtained after filtration is washed and dried under low temperature vacuum to obtain microspheres.

[0011] Step 3: Weigh the polysaccharide and cross-linking agent, add them to water and stir to dissolve them to obtain a polysaccharide polymer solution; add the microspheres to the polysaccharide polymer solution to fully impregnate them, filter and heat to dry under vacuum to obtain microspheres coated with a cross-linked polysaccharide shell.

[0012] In the above method, preferably, in step one, the degradable polymer may be selected from one or more copolymers or blends of poly(L-lactic acid) (PLLA), polyhydroxyalkanoate (PHA), polyracemic lactic acid (PDLLA), polycaprolactone (PCL), polytrimethylene carbonate (PTMC), poly(p-dioxanone) (PPDO), polyethylene glycol (PEG), polybutylene succinate (PBS), polyglycolic acid (PGA), and polylactic-co-glycolic acid copolymer (PLGA), but is not limited thereto.

[0013] In the above method, preferably, in step one, the emulsifier is selected from one or more of polyvinyl alcohol (PVA), polyethylene glycol (PEG), bis(dodecyl dimethyl ammonium bromide) (DMAB), vinylpyrrolidone (PVP), and carboxymethyl cellulose (CMC).

[0014] In the above method, preferably, the molecular weight of the biodegradable polymer is 50,000 to 500,000.

[0015] In the above method, preferably, the molecular weight of the biodegradable polymer is 50,000 to 500,000; for example: 50,000, 60,000, 70,000, 80,000, 90,000, 100,000, 110,000, 120,000, 130,000, 140,000, 150,000, 160,000, 170,000, 180,000, 190,000, 200,000, 210,000, 220,000, 230,000, 240,000, 250,000, 260,000, 270,000, 280,000, 290,000, 300,000, 310,000, 320,000, 330,000, 340,000, 350,000, 360,000, 370,000, 380,000, 390,000, 400,000, 410,000, 420,000, 430,000, 440,000, 450,000, 460,000, 470,000, 480,000, 490,000, and 500,000.

[0016] In the above method, preferably, in step one, the organic solvent may be selected from one or more combinations of dichloromethane, ethyl acetate, acetone, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, chloroform and cyclohexanone, but is not limited thereto.

[0017] In the above method, preferably, in step one, the mass concentration of the degradable polymer in the oil phase of step one is 5% to 15%; for example: 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%.

[0018] In the above method, preferably, in step one, the stirring speed is 10~100 rpm and the stirring time is 12~24 h.

[0019] In the above method, preferably, the mass concentration of polyvinyl alcohol in the aqueous phase of step one is 1% to 2%; for example: 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%.

[0020] In the above method, preferably, the heating and stirring temperature is 50~70℃ and the stirring time is 12~24h.

[0021] In the above method, preferably, in step one, the emulsification adopts a stirring method of first high speed and then low speed. The high speed stirring speed is 1000~1500 rpm, for example: 1000 rpm, 1100 rpm, 1200 rpm, 1300 rpm, 1400 rpm, 1500 rpm; the stirring time is 15 min; the low speed stirring speed is 100 rpm, and the stirring time is 12 h.

[0022] In the above method, preferably, in step one, the volume ratio of the oil phase to the water phase is 1:5 to 1:10; for example: 1:5, 1:6, 1:7, 1:8, 1:9, 1:10.

[0023] In the above method, preferably, in step two, the negative pressure condition is -100kPa to -80kPa. Specifically, this negative pressure condition needs to be adjustable, starting low and gradually increasing, until a vacuum state (-100kPa to -80kPa) is reached after the solvent is removed.

[0024] In the above method, preferably, in step two, the low-temperature vacuum drying is performed by freezing and vacuum drying at -80℃ to -20℃.

[0025] In the above method, preferably, in step two, the microspheres are further sieved through a screen to obtain microspheres with a particle size of 100~500μm.

[0026] In the above method, preferably, in step three, the polysaccharide may be selected from one or more combinations of sodium hyaluronate (HA), chitosan (CS), gelatin, collagen, silk fibroin, agar, carrageenan, pectin, cellulose, xanthan gum, gum arabic, dextran, sodium alginate, starch, and chitin; but is not limited thereto.

[0027] In the above method, preferably, in step three, the molecular weight of the polysaccharide is 800,000 to 2,500,000; for example: 800,000, 900,000, 1,000,000, 1,100,000, 1,200,000, 1,300,000, 1,400,000, 1,500,000, 1,600,000, 1,700,000, 1,800,000, 1,900,000, 2,000,000, 2,100,000, 2,200,000, 2,300,000, 2,400,000, 2,500,000.

[0028] In the above method, preferably, in step three, the crosslinking agent may be selected from one or more combinations of glutaraldehyde, 1,4-butanediol glycidyl ether (BDDGE), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), N-hydroxysuccinimide (NHS), genipin, and photosensitive crosslinking agents, but is not limited thereto.

[0029] In the above method, preferably, in step three, the mass concentration of the polysaccharide polymer solution is 1% to 20%; for example: 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%.

[0030] In the above method, preferably, in step three, the mass ratio of the polysaccharide to the crosslinking agent is 2:1 to 10:1; for example: 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1.

[0031] In the above method, preferably, in step three, the thorough impregnation is performed by ultrasonic impregnation.

[0032] In the above method, preferably, in step three, the heating vacuum drying is performed in an oven at a temperature of 40~70℃ for a drying time of 3~12h.

[0033] In the above method, preferably, in step three, the microspheres coated with the cross-linked polysaccharide shell are sieved through a screen to obtain microspheres with a particle size of 100~500μm.

[0034] On the other hand, the present invention also provides a fully degradable arterial embolization microsphere, which is prepared by the above-described preparation method.

[0035] Furthermore, the present invention also provides a method for preparing fully degradable arterial embolization drug-loaded microspheres, the method comprising the following steps:

[0036] The method for preparing fully degradable arterial embolization microspheres described above is further modified in step three by adding a drug during the preparation of the polysaccharide polymer solution, while other steps remain unchanged; thus, core-shell structured composite drug-loaded microspheres are prepared.

[0037] In the above method, preferably, the drug may be selected from one or more combinations of 5α-reductase inhibitors, α-receptor blockers, phosphodiesterase-5 inhibitors, anticholinergic drugs, and natural plant extract supplements, but is not limited thereto.

[0038] In the above method, preferably, the 5α-reductase inhibitor may be selected from one or more combinations of finasteride, dutasteride and iridaride, but is not limited thereto.

[0039] In the above method, preferably, the α-receptor blocker may be selected from one or more combinations of terazosin, doxazosin, tamsulosin, alfuzosin, and silodosin, but is not limited thereto.

[0040] In the above method, preferably, the phosphodiesterase-5 inhibitor may be selected from one or more combinations of tadalafil, sildenafil, vardenafil, udenafil, avanafil, and mironafil, but is not limited thereto.

[0041] In the above method, preferably, the anticholinergic drug may be selected from one or more combinations of oxybutynin, tolterodine, and solifenacin, but is not limited thereto.

[0042] In the above method, preferably, the plant extract natural supplement may be selected from one or more combinations of saw palmetto, African pine nut and pumpkin seed oil, but is not limited thereto.

[0043] In the above method, preferably, the mass ratio of the polysaccharide to the drug is 1:1 to 5:3; for example: 1:1, 5:3, 5:4.

[0044] Furthermore, the present invention also provides a fully degradable arterial embolization drug-loaded microsphere, which is prepared by the above-described preparation method.

[0045] In another aspect, the present invention also provides the application of the above-mentioned fully degradable arterial embolization drug-loaded microspheres or the fully degradable arterial embolization drug-loaded microspheres prepared by the above-mentioned preparation method in the preparation of drugs for treating prostate diseases.

[0046] In the above applications, preferably, the prostate disease includes one or more of benign prostatic hyperplasia, prostatitis, prostate cysts, prostate stones, and prostate abscesses, but is not limited thereto.

[0047] In another aspect, the present invention also provides a method for treating prostate diseases, which delivers the above-mentioned fully degradable arterial embolization drug-loaded microspheres via embolization.

[0048] In the above method, preferably, the prostate disease includes one or more of benign prostatic hyperplasia, prostatitis, prostate cysts, prostate stones, and prostate abscesses, but is not limited thereto.

[0049] The beneficial effects of this invention are:

[0050] In this invention, adding a polysaccharide layer helps improve the suspension and dispersibility of microspheres during injection, and also facilitates tissue adhesion and encapsulation after the microspheres enter the embolization site. Cross-linking enhances the adhesion between the polysaccharide layer and the microspheres, while preventing the outer polysaccharide material from being rapidly dissolved by water during injection, thus preventing it from losing its suspension and dispersing properties.

[0051] The microspheres prepared in this invention have good elasticity and can withstand 70% compression without rupture. They are suitable for the diameter and anatomical characteristics of the prostatic arteries. These microspheres can embolize the blood supply to the prostatic arteries using minimally invasive interventional techniques, causing necrosis and atrophy of the enlarged portion of the prostate, thereby reducing the prostate volume and improving urinary difficulties in patients with benign prostatic hyperplasia (BPH). In a canine BPH model, after embolizing the prostatic arteries with these microspheres, within one week, the central region of the prostate tissue showed a significant reduction in glandular tissue, atrophy or disappearance of acini, sparse distribution of ducts, proliferation of interstitial fibrous tissue, infiltration of a small number of lymphocytes and plasma cells, and focal aggregation of lymphocytes forming a tertiary lymphoid follicle. A small amount of embolic material was observed in an artery around the periphery of the prostate; the arterial endothelial cells were intact, the vessel lumen was patent, no thrombus formation was observed, and the vessel wall structure was normal. No abnormalities were observed in the intraprostatic veins or capillaries. Pathological findings: Emboli were found in the lumen of individual prostatic arteries; the vessel wall structure was normal; partial atrophy of the prostatic tissue was observed, accompanied by interstitial fibrous tissue proliferation and mild chronic inflammation.

[0052] The microspheres of this invention can be completely degraded and metabolized in vivo, posing no risk of long-term retention. The degradation time of the microspheres is controllable, effectively maintaining the embolization effect for up to 6 months, gradually degrading over 6 months after embolization, and completely degrading around 12 months after embolization.

[0053] The above description is merely an overview of the technical solution of the present invention. In order to better understand the technical means of the present invention and to implement it in accordance with the contents of the specification, the following describes the preferred embodiments of the present invention in detail with reference to the accompanying drawings. Attached Figure Description

[0054] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0055] Figure 1 This is a SEM image of the PLLA microspheres prepared in Example 1.

[0056] Figure 2 The image shows a SEM image of the PLLA-HA composite microspheres prepared in Example 1.

[0057] Figure 3 This is a drug release curve of the PLLA-HA composite drug-loaded microspheres prepared in Example 4.

[0058] Figure 4 This is a drug release curve of the PLLA-HA composite drug-loaded microspheres prepared in Example 5.

[0059] Figure 5 This is a drug release curve of the PLLA-HA composite drug-loaded microspheres prepared in Example 6.

[0060] Figure 6 This is a schematic diagram of interventional procedures for benign prostatic hyperplasia (BPH).

[0061] Figure 7 MRI images of the prostate before and after establishing a benign prostatic hyperplasia model.

[0062] Figure 8 Typical illustrations of arteriography before embolization (A), immediately after embolization (B), and before euthanasia (C).

[0063] Figure 9 These are MRI scans of the prostate before and after prostate artery embolization (A: before embolization, B: before execution).

[0064] Figure 10 The percentage change in prostate volume was between the experimental and control groups. Detailed Implementation

[0065] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention. The processes, conditions, reagents, experimental methods, etc., for implementing the present invention, except for the contents specifically mentioned below, are all common knowledge and general knowledge in the art, and the present invention does not have any special limitations.

[0066] definition:

[0067] The term "arterial embolization microspheres" refers to medical devices used in interventional radiology and endovascular therapy. Typically made of biocompatible materials, they are designed to be delivered via a catheter system to a target blood vessel to block or reduce blood flow. This treatment method, known as arterial embolization, is commonly used to control bleeding, treat tumors, and correct arteriovenous malformations. The arterial embolization microspheres of this invention can be loaded with chemotherapy drugs or other therapeutic agents to achieve local drug release, improve therapeutic efficacy, and reduce systemic toxicity.

[0068] The term "fully degradable" refers to a material that can be completely decomposed into harmless small molecules in vivo or under specific environmental conditions, and ultimately absorbed or excreted by the body. In this invention, fully degradable arterial embolization microspheres refer to those microspheres that can be completely degraded and metabolized by the body within a predetermined time.

[0069] The term "core-shell structure" refers to a composite material structure with a defined core and shell. In this structure, the core is encapsulated by one or more layers of different materials, forming a complete microsphere or particle. This structure is very useful in a variety of applications because it combines the advantages of different materials to achieve specific functions. Core-shell structures can be used for drug delivery, controlled release, and improved biocompatibility, among other applications. In this invention, microspheres serve as the core structure, and biocompatible degradable polysaccharides serve as the shell structure, for use in a drug delivery system. The release rate of the drug is controlled by the shell material to achieve local or systemic therapy.

[0070] The term "degradable polymers" refers to a class of high-molecular-weight materials that can be gradually broken down in the human body through hydrolysis, enzymatic hydrolysis, or other biochemical processes, and are ultimately completely absorbed or metabolized into harmless substances by the body. These materials are designed to temporarily block or reduce blood supply to the site of disease, thereby achieving therapeutic purposes such as controlling bleeding, treating tumors, eliminating inflammation, and correcting arteriovenous malformations.

[0071] The term "emulsifier" refers to a substance that can improve the surface tension between the various constituent phases in an emulsion, thereby forming a homogeneous and stable dispersion system or emulsion. These are surfactants, whose molecules contain both hydrophilic and lipophilic groups. This allows emulsifiers to aggregate at the oil-water interface, stabilizing and increasing the energy of the emulsion by reducing interfacial tension and decreasing the energy required to form the emulsion. The polyvinyl alcohol (PVA) used in this invention is a medical excipient approved by the US FDA for clinical use. It possesses properties such as being non-toxic, harmless, biocompatible, and suitable as a drug carrier.

[0072] The term "emulsion" refers to a mixture of two immiscible liquids, one of which is dispersed in the other as tiny droplets. In this invention, an emulsion refers to a mixture of oil and water, one as a dispersed phase (existing as tiny droplets) and the other as a continuous phase (surrounding the droplets of the dispersed phase); particularly, it is a mixture of an oil phase of biodegradable polymer dissolved in an organic solvent and an aqueous phase of polyvinyl alcohol dissolved in water.

[0073] The term "polysaccharide" refers to an important class of biological macromolecules, which are high-molecular-weight compounds composed of ten or more monosaccharide units linked by glycosidic bonds. These monosaccharide units can be the same (homopyrans) or different (heteropyrans). Polysaccharides are widely distributed in nature and are one of the main components of the cell walls of plants, animals, and microorganisms. Polysaccharides play a variety of important physiological roles in organisms, including energy storage, structural support, and signal transduction. In the fields of medicine and biomaterials, polysaccharides are widely used due to their good biocompatibility, biodegradability, and diverse functionalities.

[0074] The term "crosslinking" refers to the process of linking two or more molecules together through chemical bonds to form a more complex network structure. In the crosslinking of polysaccharides into embolic microspheres to form a core-shell structure in this invention, crosslinking refers to connecting specific groups between polysaccharide molecules or with other materials through a chemical reaction, thereby forming a stable three-dimensional network structure.

[0075] The term "curing" refers to the process by which a material changes from a liquid or semi-solid state to a solid state through physical or chemical processes. In this invention, stirring the emulsion under negative pressure removes the liquid components (such as organic solvents) from the emulsion, thereby allowing the solid components (such as polymers or cross-linked networks) in the emulsion to form a stable solid structure.

[0076] The term "low-temperature vacuum drying" refers to a drying technique performed under low-temperature (typically -20°C or lower) and vacuum conditions. This method removes moisture from the material by freezing it below its freezing point and then allowing the ice to sublimate directly into water vapor in a vacuum environment. This method is particularly suitable for heat-sensitive materials, effectively preserving their structure and activity.

[0077] The term "benign prostatic hyperplasia (BPH)," also known as benign prostatic hyperplasia (BPH), is a common male urological disease that primarily affects middle-aged and older men. It refers to the non-cancerous enlargement of the prostate gland, leading to an increased prostate volume that compresses the urethra and causes a range of lower urinary tract symptoms (LUTS).

[0078] The term "prostatitis" refers to inflammation of the prostate gland, a common male urological disease. Prostatitis can be caused by a variety of factors, including bacterial infection, non-bacterial factors (such as immune responses, neuromuscular dysfunction, etc.), and other unknown causes. Based on etiology and clinical manifestations, prostatitis can be classified into types such as acute bacterial prostatitis (ABP), chronic bacterial prostatitis (CBP), chronic prostatitis / chronic pelvic pain syndrome (CP / CPPS), and asymptomatic inflammatory prostatitis (AIP).

[0079] The term "prostatic cyst" refers to a fluid-filled sac-like structure that forms within the prostate gland. These cysts are usually benign and can be congenital (related to developmental abnormalities) or acquired (caused by inflammation, infection, or other factors). Prostatic cysts can be classified into types such as congenital prostatic cysts and acquired prostatic cysts based on their cause and location.

[0080] The term "prostatic calculi" refers to calcifications that form within the prostate tissue or prostate ducts. These calculi are typically small, hard particles composed primarily of calcium phosphate, calcium oxalate, or other minerals. Prostatic calculi can be single or multiple and are generally considered benign.

[0081] The term "prostatic abscess" refers to a sac-like structure filled with pus that forms within the prostate tissue. This abscess is usually caused by a bacterial infection, leading to inflammation, necrosis, and pus accumulation in the local tissue. Prostatic abscess is a relatively rare but serious condition that requires timely diagnosis and treatment to avoid complications.

[0082] The term "5α-reductase inhibitors" refers to a class of drugs that reduce the conversion of testosterone to dihydrotestosterone (DHT) by inhibiting the activity of the enzyme 5α-reductase. 5α-reductase is a key enzyme that catalyzes the conversion of testosterone to DHT, a potent androgen that plays a significant role in benign prostatic hyperplasia and androgenetic alopecia. By inhibiting this conversion process, 5α-reductase inhibitors can lower DHT levels, thereby alleviating or reversing DHT-induced symptoms.

[0083] The term "alpha-blockers" refers to a class of drugs that relax vascular smooth muscle and the smooth muscle of the prostate and bladder neck by blocking alpha-adrenergic receptors in the adrenergic nervous system. This effect can lead to vasodilation, lower blood pressure, and improved urine flow, thus reducing lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH).

[0084] The term "phosphodiesterase type 5 inhibitors" refers to a class of drugs that selectively inhibit the activity of phosphodiesterase type 5 (PDE5), thereby increasing the level of intracellular cyclic guanosine monophosphate (cGMP). cGMP is an important second messenger molecule that plays a crucial role in smooth muscle relaxation. PDE5 inhibitors, by inhibiting PDE5 activity, prevent the breakdown of cGMP, thereby increasing cGMP concentration, promoting smooth muscle relaxation and vasodilation, enhancing blood flow to the corpora cavernosa of the penis, and helping to achieve and maintain an erection; in addition, they can be used to improve lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH).

[0085] The term "anticholinergic drugs" refers to a class of medications that block the effects of acetylcholine (ACh) in the nervous system. Acetylcholine is an important neurotransmitter that functions primarily in the central and peripheral nervous systems. Anticholinergic drugs work by binding to acetylcholine receptors, preventing the interaction between acetylcholine and its receptors, thereby producing a range of pharmacological effects. They are used to treat overactive bladder (OAB) and reduce symptoms such as urinary urgency, frequency, and incontinence.

[0086] The term "plant extracts and natural supplements" refers to active ingredients or mixtures thereof extracted from plants and used to supplement diet, improve health, or treat specific conditions. These supplements typically contain a variety of bioactive compounds, such as flavonoids, saponins, fatty acids, and polyphenols, possessing various biological activities including antioxidant, anti-inflammatory, and immunomodulatory effects. In the field of prostate health, saw palmetto, African nutmeg, and pumpkin seed oil are some common plant extract natural supplements. Saw palmetto extract is often used to treat benign prostatic hyperplasia (BPH), reducing symptoms such as urinary frequency, urgency, and nocturia, and has some anti-inflammatory effects, helping to alleviate prostate inflammation. African nutmeg extract is also commonly used to treat BPH, improving urine flow and reducing prostate volume, and has anti-inflammatory and antioxidant effects, helping to alleviate prostate inflammation. Pumpkin seed oil is believed to help maintain prostate health and can alleviate BPH symptoms.

[0087] Example 1:

[0088] This embodiment provides a core-shell structured PLLA-HA composite microsphere and its preparation method, the specific steps of which are as follows:

[0089] (1) Weigh 10g of poly-L-lactic acid (PLLA) with a weight average molecular weight of 200,000 and add it to 100mL of dichloromethane. Stir at 100rpm for 24h until it is evenly dissolved to obtain a PLLA organic solution with a mass concentration of 10%, which is used as the oil phase.

[0090] (2) Weigh 2g of polyvinyl alcohol (PVA) and add it to 100mL of water. Heat to 70℃ and stir to dissolve for 24h to obtain a uniform PVA aqueous solution with a mass concentration of 2%. After cooling, use it as the aqueous phase.

[0091] (3) Emulsification and curing: The oil phase in step (1) is slowly added to the water phase in the stirring. The volume ratio of oil phase to water phase is 1:10. First, the oil phase is stirred at high speed of 1000~1500rpm for 15min, and then stirred at low speed of 100rpm for 12h. After standing, the PLLA microspheres are collected.

[0092] (4) Weigh 0.5g of sodium hyaluronate with a molecular weight of 1,000,000 to 1,500,000 and add it to 10mL of water. Stir for 2 hours until completely dissolved. Then add 0.25g of 1,4-butanediol glycidyl ether and stir for 15 minutes to obtain a mixed solution. Add PLLA microspheres to the above mixed solution, sonicate to wet, and collect the composite microspheres after standing.

[0093] (5) Place the composite microspheres in a 50°C oven and vacuum dry for 5 hours until the mass remains unchanged, so that sodium hyaluronate forms a cross-linked composite layer on the outside of the PLLA microspheres. After passing through a 150-mesh sieve, collect the PLLA-HA composite microspheres with sodium hyaluronate core-shell structure.

[0094] Scanning electron microscopy (SEM) experiments were performed on the PLLA microspheres and PLLA-HA composite microspheres prepared in Example 1. The experimental results are as follows: Figure 1 and Figure 2 As shown, Figure 1 SEM image of the PLLA microspheres prepared in Example 1; Figure 2 The image shows a SEM image of the PLLA-HA composite microspheres prepared in Example 1.

[0095] Depend on Figure 1 and Figure 2 It can be seen that the surface of the PLLA-HA composite microspheres is cross-linked with a polysaccharide shell, while the surface of the PLLA microspheres is smooth.

[0096] Sedimentation experiments were conducted on PLLA microspheres and PLLA-HA composite microspheres, specifically as follows:

[0097] Different microspheres were dispersed in physiological saline, and their sedimentation time was measured using a multiple light scattering instrument at 25°C. The experimental results showed that the sedimentation time of ordinary microspheres was 15 seconds, while that of composite microspheres was 120 seconds.

[0098] This demonstrates that PLLA-HA composite microspheres exhibit improved hydrophilicity compared to ordinary PLLA microspheres. When added to physiological saline for clinical use, the composite microspheres disperse more easily and do not aggregate to clog the needle. The microspheres also exhibit improved suspension properties: after being thoroughly mixed in physiological saline, the settling time increases from 15 seconds to 120 seconds.

[0099] Example 2:

[0100] This embodiment provides a core-shell structured PLLA-CS composite microsphere and its preparation method, the specific steps of which are as follows:

[0101] (1) Weigh 10g of poly-L-lactic acid (PLLA) with a weight average molecular weight of 200,000 and add it to 100mL of dichloromethane. Stir at 100rpm for 24h until it is evenly dissolved to obtain a PLLA organic solution with a mass concentration of 10%, which is used as the oil phase.

[0102] (2) Weigh 2g of polyvinyl alcohol (PVA) and add it to 100mL of water. Heat to 70℃ and stir to dissolve for 24h to obtain a uniform PVA aqueous solution with a mass concentration of 2%. After cooling, use it as the aqueous phase.

[0103] (3) Emulsification and curing: The oil phase in step (1) is slowly added to the water phase in the stirring. The volume ratio of oil phase to water phase is 1:10. First, the oil phase is stirred at high speed of 1000~1500rpm for 15min, and then stirred at low speed of 100rpm for 12h. After standing, the PLLA microspheres are collected.

[0104] (4) Weigh 0.5g of chitosan (CS) with a molecular weight of 1,000,000 to 1,500,000 and add it to 10mL of 1% acetic acid aqueous solution. Stir for 2h until completely dissolved. Then add 0.05g of glutaraldehyde and stir for 15min to obtain a mixed solution. Add PLLA microspheres to the above mixed solution, sonicate and collect the composite microspheres after standing.

[0105] (5) Place the composite microspheres in a 50°C oven and vacuum dry for 5 hours until the mass remains unchanged, so that chitosan forms a cross-linked composite layer on the outside of the PLLA microspheres. After passing through a 150-mesh sieve, collect the PLLA-CS composite microspheres with chitosan core-shell structure.

[0106] Example 3:

[0107] This embodiment provides a core-shell structured PLLA-gelatin composite microsphere and its preparation method, the specific steps of which are as follows:

[0108] (1) Weigh 10g of poly-L-lactic acid (PLLA) with a weight average molecular weight of 200,000 and add it to 100mL of dichloromethane. Stir at 100rpm for 24h until it is evenly dissolved to obtain a PLLA organic solution with a mass concentration of 10%, which is used as the oil phase.

[0109] (2) Weigh 2g of polyvinyl alcohol (PVA) and add it to 100mL of water. Heat to 70℃ and stir to dissolve for 24h to obtain a uniform PVA aqueous solution with a mass concentration of 2%. After cooling, use it as the aqueous phase.

[0110] (3) Emulsification and curing: The oil phase in step (1) is slowly added to the water phase in the stirring. The volume ratio of oil phase to water phase is 1:10. First, the oil phase is stirred at high speed of 1000~1500rpm for 15min, and then stirred at low speed of 100rpm for 12h. After standing, the PLLA microspheres are collected.

[0111] (4) Weigh 0.5g of gelatin with a molecular weight of 100,000 and add it to 10mL of water. Heat at 50℃ and stir for 2h until completely dissolved. After cooling, add 0.05g of glutaraldehyde and stir for 15min to obtain a mixed solution. Add PLLA microspheres to the above mixed solution, sonicate to wet, and collect the composite microspheres after standing.

[0112] (5) Place the composite microspheres in a 50°C oven and vacuum dry for 5 hours until the mass remains unchanged, so that the gelatin forms a cross-linked composite layer on the outside of the PLLA microspheres. After passing through a 150-mesh sieve, collect the PLLA-gelatin composite microspheres with a gelatin core-shell structure.

[0113] Example 4:

[0114] This embodiment provides a PLLA-HA drug-loaded composite microsphere with a core-shell structure and its preparation method, the specific steps of which are as follows:

[0115] (1) Weigh 10g of poly-L-lactic acid (PLLA) with a weight average molecular weight of 200,000 and add it to 100mL of dichloromethane. Stir at 100rpm for 24h until it is evenly dissolved to obtain a PLLA organic solution with a mass concentration of 10%, which is used as the oil phase.

[0116] (2) Weigh 2g of polyvinyl alcohol (PVA) and add it to 100mL of water. Heat to 70℃ and stir to dissolve for 24h to obtain a uniform PVA aqueous solution with a mass concentration of 2%. After cooling, use it as the aqueous phase.

[0117] (3) Emulsification and curing: The oil phase in step (1) is slowly added to the water phase in the stirring. The volume ratio of oil phase to water phase is 1:10. First, the oil phase is stirred at high speed of 1000~1500rpm for 15min, and then stirred at low speed of 100rpm for 12h. After standing, the PLLA microspheres are collected.

[0118] (4) Weigh 0.5g of sodium hyaluronate with a molecular weight of 800,000 and add it to 10mL of water. Stir for 2 hours until completely dissolved. Add 0.3g of tamsulosin, then add 0.15g of 1,4-butanediol glycidyl ether and stir for 15 minutes to obtain a mixed solution. Add PLLA microspheres to the above mixed solution, sonicate to wet, and collect the composite drug-loaded microspheres after standing.

[0119] (5) The composite drug-loaded microspheres were placed in a 50°C oven and vacuum dried for 5 hours until the mass remained unchanged, so that sodium hyaluronate formed a cross-linked composite layer on the outside of the PLLA microspheres. After passing through a 150-mesh sieve, the PLLA-HA composite drug-loaded microspheres with sodium hyaluronate core-shell structure were collected.

[0120] Weigh 2g of the drug-loaded microspheres into a sample vial, add 500mL of phosphate buffer, place in a 37℃ constant temperature test chamber, take samples daily and test the drug concentration in the solution using high performance liquid chromatography, and calculate the drug release amount.

[0121] The drug release curve of the PLLA-HA composite drug-loaded microspheres is as follows: Figure 3 As shown, by Figure 3 It can be seen that, in addition to increasing hydrophilic suspension, the drug can be stably released for 7 days.

[0122] Example 5:

[0123] This embodiment provides a PLLA-HA drug-loaded composite microsphere with a core-shell structure and its preparation method, the specific steps of which are as follows:

[0124] (1) Weigh 10g of poly-L-lactic acid (PLLA) with a weight average molecular weight of 200,000 and add it to 100mL of dichloromethane. Stir at 100rpm for 24h until it is evenly dissolved to obtain a PLLA organic solution with a mass concentration of 10%, which is used as the oil phase.

[0125] (2) Weigh 2g of polyvinyl alcohol (PVA) and add it to 100mL of water. Heat to 70℃ and stir to dissolve for 24h to obtain a uniform PVA aqueous solution with a mass concentration of 2%. After cooling, use it as the aqueous phase.

[0126] (3) Emulsification and curing: The oil phase in step (1) is slowly added to the water phase in the stirring. The volume ratio of oil phase to water phase is 1:10. First, the oil phase is stirred at high speed of 1000~1500rpm for 15min, and then stirred at low speed of 100rpm for 12h. After standing, the PLLA microspheres are collected.

[0127] (4) Weigh 0.5g of sodium hyaluronate with a molecular weight of 1,000,000 to 1,500,000 and add it to 10mL of water. Stir for 2 hours until completely dissolved. Add 0.5g of finasteride, then add 0.25g of 1,4-butanediol glycidyl ether and stir for 15 minutes to obtain a mixed solution. Add PLLA microspheres to the above mixed solution, sonicate to wet, and collect the composite drug-loaded microspheres after standing.

[0128] (5) The composite drug-loaded microspheres were placed in a 50°C oven and vacuum dried for 5 hours until the mass remained unchanged, so that sodium hyaluronate formed a cross-linked composite layer on the outside of the PLLA microspheres. After passing through a 150-mesh sieve, the PLLA-HA composite drug-loaded microspheres with sodium hyaluronate core-shell structure were collected.

[0129] Weigh 2g of the drug-loaded microspheres into a sample vial, add 500mL of phosphate buffer, place in a 37℃ constant temperature test chamber, take samples daily and test the drug concentration in the solution using high performance liquid chromatography, and calculate the drug release amount.

[0130] The drug release curve of the PLLA-HA composite drug-loaded microspheres is as follows: Figure 4 As shown, by Figure 4 It can be seen that, in addition to increasing hydrophilic suspension, the drug can be stably released for 15 days.

[0131] Example 6:

[0132] This embodiment provides a PLLA-HA drug-loaded composite microsphere with a core-shell structure and its preparation method, the specific steps of which are as follows:

[0133] (1) Weigh 10g of poly-L-lactic acid (PLLA) with a weight average molecular weight of 200,000 and add it to 100mL of dichloromethane. Stir at 100rpm for 24h until it is evenly dissolved to obtain a PLLA organic solution with a mass concentration of 10%, which is used as the oil phase.

[0134] (2) Weigh 2g of polyvinyl alcohol (PVA) and add it to 100mL of water. Heat to 70℃ and stir to dissolve for 24h to obtain a uniform PVA aqueous solution with a mass concentration of 2%. After cooling, use it as the aqueous phase.

[0135] (3) Emulsification and curing: The oil phase in step (1) is slowly added to the water phase in the stirring. The volume ratio of oil phase to water phase is 1:10. First, the oil phase is stirred at high speed of 1000~1500rpm for 15min, and then stirred at low speed of 100rpm for 12h. After standing, the PLLA microspheres are collected.

[0136] (4) Weigh 0.5g of sodium hyaluronate with a molecular weight of 2,000,000 to 2,500,000 and add it to 10mL of water. Stir for 2 hours until completely dissolved. Add 0.5g of dutasteride and then add 0.45g of 1,4-butanediol glycidyl ether. Stir for 15 minutes to obtain a mixed solution. Add PLLA microspheres to the above mixed solution, sonicate to wet, and collect the composite drug-loaded microspheres after standing.

[0137] (5) The composite drug-loaded microspheres were placed in a 50°C oven and vacuum dried for 5 hours until the mass remained unchanged, so that sodium hyaluronate formed a cross-linked composite layer on the outside of the PLLA microspheres. After passing through a 150-mesh sieve, the PLLA-HA composite drug-loaded microspheres with sodium hyaluronate core-shell structure were collected.

[0138] Weigh 2g of the drug-loaded microspheres into a sample vial, add 500mL of phosphate buffer, place in a 37℃ constant temperature test chamber, take samples daily and test the drug concentration in the solution using high performance liquid chromatography, and calculate the drug release amount.

[0139] The drug release curve of the PLLA-HA composite drug-loaded microspheres is as follows: Figure 5 As shown, by Figure 5 It can be seen that:

[0140] In addition to increasing hydrophilic suspension, it can stably release drugs for 30 days.

[0141] Example 7: Animal Experiment of Transcarotid Prostate Embolization via Internal Carotid Artery

[0142] The sodium hyaluronate core-shell structured PLLA-HA composite microspheres (i.e., embolization microspheres) prepared in Example 1 of this invention were used to prepare a suspension with sodium chloride injection (0.9%), and formulated into a 1000 mg / vial composite microsphere formulation, which was used as the test sample for animal experiments as follows.

[0143] 1. Laboratory animals:

[0144] Table 1-1 Animal Information

[0145]

[0146] The experimental animals were housed in a model animal care center, with room temperature controlled at 20–26℃, humidity at 40–70%, and 12 hours of lighting followed by 12 hours of darkness. They were housed individually in standardized galvanized steel pipe cages, one animal per cage. Animals were fed and watered according to SOP requirements. The feed used was standardized dog food produced by Keao Xieli (Tianjin) Feed Co., Ltd., and the drinking water met national standards (GB5749-2022, Standard for Drinking Water Quality).

[0147] 2. Construction of a benign prostatic hyperplasia model:

[0148] Experimental animals are provided by qualified suppliers and undergo quarantine at the facility at least 7 days in advance to acclimatize to the environment and reduce stress. A veterinarian conducts a pre-experiment health check to ensure the animals are healthy; any animals exhibiting abnormal behavioral characteristics or symptoms before modeling are excluded from the experiment. Experimental animals are fasted for 12 hours and deprived of water for 6 hours before the experiment.

[0149] Before the experiment, the patient was weighed and anesthesia was induced according to standard laboratory procedures. Blood was drawn for complete blood count and blood biochemistry tests, and an MRI was performed to measure the prostate volume. After the scan, castration (removal of the testis) was performed. Three days after castration, the patient was given penicillin for anti-infection treatment, once a day.

[0150] Following castration, testosterone propionate (2.5 mg / kg) was administered intramuscularly once daily for at least 3 months. An MRI was performed again after the injections were completed and before embolization to measure prostate volume and confirm successful modeling.

[0151] 3. Experimental Grouping:

[0152] This study employed a randomized, negative-control experimental design. All animals with benign prostatic hyperplasia (BPH) models were randomly divided into an experimental group and a control group. The experimental group underwent prostatic arteriography followed by injection of fully degradable embolization microspheres for prostatic microsphere embolization, while the control group underwent only prostatic arteriography without embolization. Based on the duration of embolization, the experimental and control groups were further divided into a 1-month postoperative group, a 3-month postoperative group, and a 6-month postoperative group.

[0153] Table 3-1 Experimental Group Design

[0154]

[0155] 4.1 Prostatic arteriography:

[0156] After successful modeling, the experimental and control animals were anesthetized, and blood samples were collected for complete blood count and blood biochemistry tests. The surgical area was shaved and disinfected, draped with sterile towels, and local anesthesia with 0.1% lidocaine was administered at the cervical cannulation site. A 1cm incision was made in the skin at the right carotid artery, and the subcutaneous tissue and muscle were dissected layer by layer to isolate the right common carotid artery. A 4F catheter sheath was inserted using the Seldinger technique. Under fluoroscopic guidance, a 4F Cordis catheter was inserted through the catheter sheath into the abdominal aorta, and bilateral internal iliac artery angiography was performed. The location and morphology of the prostatic artery openings were observed, and the catheter position and direction were adjusted to the bilateral prostatic arteries. Based on the angiography results, a microcatheter was introduced into the bilateral prostatic blood supply arteries of the dog, and contrast agent was injected to confirm the distribution of prostatic vessels.

[0157] 4.2 Prostatic microsphere embolization:

[0158] In the control group, the procedure ended after prostate arteriography, while in the experimental group, embolization therapy began after arteriography confirmed the location. Under fluoroscopic guidance, experimentally tested fully degradable embolization microspheres were slowly embolized into the prostate artery. Dynamic observation was maintained under fluoroscopy during embolization, and injection was discontinued when micro-reflux of the contrast agent occurred and forward blood flow ceased. Close monitoring for reflux was maintained to prevent accidental embolization of other vessels. After embolization, another angiography was performed to confirm complete embolization of the prostate's blood supply artery. The contralateral prostate artery was then treated using the same method. After embolization, all catheters and catheter sheaths were removed, and the puncture site was sutured with a purse-string suture for hemostasis. Figure 6 As shown, the black arrows illustrate the course of the catheter sheath / microcatheter from the abdominal aorta to the prostate's blood supply artery.

[0159] 5.1 Postoperative treatment and maintenance of the pathological model:

[0160] For 7 days after embolization, penicillin was injected intramuscularly daily for anti-infection treatment. The presence of hematoma at the puncture site, as well as the animal's mental state, appetite, defecation, and urination, were observed. The experimental and control animals continued to receive intramuscular injections of testosterone propionate (1 mg / kg / day) until the animals were sacrificed for tissue sampling to maintain the pathological model of benign prostatic hyperplasia.

[0161] 5.2 MRI and angiography examinations:

[0162] Blood samples were collected again from both groups of test animals at the corresponding time points (1, 3, and 6 months post-surgery) for routine blood tests and blood biochemistry examinations, and prostate MRI was performed again to measure prostate volume. Angiography was performed on the prostate artery of the test animals in the experimental group to observe the recanalization status.

[0163] 5.3 Post-execution observation

[0164] After completing the above-mentioned MRI and angiography examinations, the test animals were euthanized. The prostate, rectum, kidneys, ureters, bladder, and vas deferens were grossly observed and samples were taken for histopathological examination to evaluate the chronic inflammatory response and tissue cell response. The prostate was dissected for histopathological examination to evaluate the degradation of the microspheres implanted in the prostate.

[0165] 5.4 Evaluation Indicators:

[0166] 5.4.1, Change rate of prostate volume

[0167] Two groups of test animals underwent MRI examinations of the prostate before modeling, before embolization, and at 1, 3, and 6 months after embolization. Radiologists measured the three diameters of the prostate (superior-inferior diameter, anteroposterior diameter, and lateral diameter), and the average of two measurements for each diameter was taken to calculate the prostate volume (PV).

[0168]

[0169] Successful modeling criteria: prostate volume greater than 15cm 3 A successful model is defined as an increase of more than 40%, meaning the prostate volume before embolization is greater than 15 cm. 3 Or the prostate volume before embolization increased by more than 40% compared to the prostate volume before modeling.

[0170] The changes in prostate volume at various time points (1, 3, and 6 months) after embolization were evaluated compared to baseline volume (before embolization).

[0171]

[0172] 5.4.2 Hematological examination:

[0173] Blood samples were collected before modeling, embolization, and tissue sampling. Routine blood parameters were measured using a fully automated blood cell analyzer, and biochemical parameters were measured using a fully automated biochemical analyzer. The test results were statistically analyzed.

[0174] 5.4.3 Gross Anatomical Observation

[0175] After the experimental animals were euthanized, gross anatomical observations were performed on the prostate, rectum, kidneys, ureters, bladder, and vas deferens to observe for abnormal redness and swelling, ulceration and bleeding, perforation, necrosis, ectopic embolism, infection, infarct foci, and other abnormal manifestations.

[0176] 5.4.4 Pathological examination

[0177] (a) Histopathological examination

[0178] The gross specimens were fixed in 10% formalin and then stained with hematoxylin-eosin (HE) staining. Tissue necrosis, inflammatory response, and tissue repair were evaluated. Cellular and tissue responses were scored according to the histological evaluation system in Appendix E of GB / T 16886.6-2022, and local biological evaluation was performed using a semi-quantitative scoring system.

[0179] (b) Evaluation of microsphere degradation

[0180] During histopathological examination, the diameter of undegraded microspheres in the tissue is observed and measured under a microscope (eight microspheres are randomly selected from the field of view and their diameters are measured; if eight microspheres are not observed in the field of view, the diameters of all microspheres in the field of view are measured).

[0181] 6. Results and Conclusions:

[0182] 6.1 Overall Experimental Situation

[0183] A total of 21 experimental animals were used in this study, including 12 animals in the experimental group (n=3 at 1 month post-surgery, n=3 at 3 months post-surgery, and n=6 at 6 months post-surgery) and 9 animals in the control group (n=3 at 1 month post-surgery, n=3 at 3 months post-surgery, and n=3 at 6 months post-surgery). There was no significant difference in average body weight between the experimental and control groups at the start of the experiment (13.83±1.75 kg vs 13.80±1.56 kg, P=0.9734). The benign prostatic hyperplasia model was successfully established according to the protocol, and prostatic arteriography and prostatic microsphere embolization were successfully completed. All animals survived to the corresponding research endpoint and underwent euthanasia after completing the corresponding MRI examinations and tests. Organ tissues were successfully collected and pathologically examined according to the protocol.

[0184] 6.2 Establishment of a Benign Prostatic Hyperplasia Model

[0185] After undergoing MRI scans and castration, testosterone propionate was continuously injected into the testosterone propionate for at least 3 months. MRI scans were then performed again to observe changes in prostate volume before and after these procedures. Figure 7 (A: Before modeling; B: After modeling). The prostate volume of each test animal increased by more than 40% compared to before modeling, confirming successful modeling.

[0186] 6.3. Change rate of prostate volume

[0187] The control group underwent surgery after prostate arteriography, while the experimental group underwent prostate artery microsphere embolization. Animals in each group were observed until sacrifice at the designated time points, at which point prostate arteriography was performed again. Figure 8 The black arrows indicate the contrast agent transection points of the prostatic artery and surrounding feeding arteries after embolization, while the white boxes indicate the minimal recanalization of neovascularization around the prostate and the original feeding arteries several months post-embolization. Both groups of animals underwent repeat MRI examinations of the prostate before sacrifice at corresponding time points (1, 3, and 6 months post-procedure). Figure 9 The radiologist measured the anteroposterior diameter (abdomen and back), superior-inferior diameter (head and tail), and left-right diameter of the prostate, calculated the prostate volume, evaluated the changes in prostate volume at each time point, and compared it with the corresponding baseline volume to calculate the rate of change in volume.

[0188] Depend on Figure 9 It can be seen that the volume change rates in the experimental group at 1 month, 3 months, and 6 months post-surgery were 40.34±21.91%, 47.87±22.59%, and 63.30±16.98%, respectively. Correspondingly, the volume change rates in the control group were 123.79±35.75%, 113.45±24.74%, and 148.81±38.63%, respectively. Figure 10There was no significant difference in the volume change rate among the three postoperative time points (1 month, 3 months, and 6 months) in the experimental group (F=1.56, P=0.2611).

[0189] in conclusion

[0190] The application of fully degradable embolized microspheres in a beagle dog model of benign prostatic hyperplasia is safe and effective; the prostate volume is reduced by 36.70% to 59.66% compared with the preoperative volume, and the efficacy is comparable from 1 month to 6 months after surgery.

[0191] Specific embodiments have been used to illustrate the principles and implementation methods of this invention. The descriptions of the embodiments above are only for the purpose of helping to understand the method and core ideas of this invention. At the same time, for those skilled in the art, there will be changes in the specific implementation methods and application scope based on the ideas of this invention. Therefore, the content of this specification should not be construed as a limitation of this invention.

Claims

1. A method for preparing fully degradable arterial embolization microspheres, characterized in that, Includes the following steps: Step 1: Weigh the biodegradable polymer and add it to an organic solvent and stir to dissolve, obtaining the oil phase; weigh the emulsifier and add it to water and heat and stir to dissolve, obtaining the aqueous phase; slowly add the oil phase to the aqueous phase, using a stirring method of high speed first and then low speed to fully emulsify the oil phase in the aqueous phase to form an emulsion; Step 2: Under negative pressure, the emulsion is stirred to evaporate the organic solvent and solidify. The solid obtained after filtration is washed and dried under low temperature vacuum to obtain microspheres. Step 3: Weigh the polysaccharide and cross-linking agent, add them to water and stir to dissolve them to obtain a polysaccharide polymer solution; add the microspheres to the polysaccharide polymer solution to fully impregnate them, filter and heat to dry under vacuum to obtain microspheres coated with a cross-linked polysaccharide shell.

2. The method according to claim 1, characterized in that: In step one, the biodegradable polymer is selected from one or more copolymers or blends of poly(L-lactic acid) (PLLA), polyhydroxyalkanoate (PHA), polyracemic lactic acid (PDLLA), polycaprolactone (PCL), polytrimethylene carbonate (PTMC), poly(p-dioxanone) (PPDO), polyethylene glycol (PEG), polybutylene succinate (PBS), polyglycolic acid (PGA), and polylactic-co-glycolic acid copolymer (PLGA). Preferably, the molecular weight of the biodegradable polymer is 50,000 to 500,000.

3. The method according to claim 1, characterized in that: In step one, the emulsifier is selected from one or more of polyvinyl alcohol (PVA), polyethylene glycol (PEG), bis(dodecyl dimethyl ammonium bromide) (DMAB), vinylpyrrolidone (PVP), and carboxymethyl cellulose (CMC).

4. The method according to claim 1, characterized in that: In step one, the organic solvent is selected from one or more combinations of dichloromethane, ethyl acetate, acetone, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, chloroform, and cyclohexanone.

5. The method according to claim 1 or 2, characterized in that: In the oil phase of step one, the mass concentration of the biodegradable polymer is 5% to 15%. Preferably, the stirring speed is 10~100 rpm and the stirring time is 12~24 h.

6. The method according to claim 1, characterized in that: In the aqueous phase of step one, the mass concentration of the polyvinyl alcohol is 1% to 2%. Preferably, the heating and stirring temperature is 50~70℃, and the stirring time is 12~24h.

7. The method according to claim 1, characterized in that: In step one, emulsification is carried out by stirring at high speed first and then at low speed. The high speed stirring speed is 1000~1500 rpm and the stirring time is 1-15 min; the low speed stirring speed is 10-100 rpm and the stirring time is 2-12 h.

8. The method according to claim 1, characterized in that: In step one, the volume ratio of the oil phase to the water phase is 1:5 to 1:

10.

9. The method according to claim 1, characterized in that: In step two, the negative pressure condition is -100kPa to -80kPa.

10. The method according to claim 1, characterized in that: In step two, low-temperature vacuum drying involves freezing and vacuum drying at -80℃ to -20℃.

11. The method according to claim 1, characterized in that: In step two, the microspheres are further sieved through a screen to obtain microspheres with a particle size of 100~500μm.

12. The method according to claim 1, characterized in that: In step three, the polysaccharide is selected from one or more combinations of sodium hyaluronate (HA), chitosan (CS), gelatin, collagen, silk fibroin, agar, carrageenan, pectin, cellulose, xanthan gum, gum arabic, dextran, sodium alginate, starch, and chitin. Preferably, the polysaccharide has a molecular weight of 800,000 to 2,500,000.

13. The method according to claim 1, characterized in that: In step three, the crosslinking agent is selected from one or more combinations of glutaraldehyde, 1,4-butanediol glycidyl ether (BDDGE), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), N-hydroxysuccinimide (NHS), genipin, and photosensitive crosslinking agents.

14. The method according to claim 1 or 11, characterized in that: In step three, the mass concentration of the polysaccharide polymer solution is 1% to 20%.

15. The method according to claim 1, 12, or 13, characterized in that: In step three, the mass ratio of the polysaccharide to the crosslinking agent is 2:1 to 10:

1.

16. The method according to claim 1, characterized in that: In step three, thorough impregnation is achieved using ultrasonic impregnation.

17. The method according to claim 1, characterized in that: In step three, the heating vacuum drying is performed in an oven at a temperature of 40~70℃ for 3~12 hours.

18. The method according to claim 1, characterized in that: In step three, the microspheres coated with the cross-linked polysaccharide shell are sieved through a screen to obtain microspheres with a particle size of 100~500μm.

19. A fully degradable arterial embolization microsphere, prepared by the preparation method according to any one of claims 1 to 18.

20. The use of the fully degradable arterial embolization microspheres of claim 19 or the fully degradable arterial embolization microspheres prepared by any one of claims 1 to 18 in the preparation of a medicament for treating prostate diseases.

21. The application according to claim 20, characterized in that: The prostate diseases include one or more of the following: benign prostatic hyperplasia, prostatitis, prostatic cysts, prostatic stones, and prostatic abscess.

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