Bone marrow cavity targeted drug release microspheres

Abstract

The application discloses a bone marrow cavity targeted drug release microsphere and belongs to the technical field of medical devices. The drug release microsphere is spherical in structure and contains drugs, and can be implanted into the inside of a bone marrow cavity. The spherical structure is suitable for the microenvironment of the bone marrow cavity, and after implantation, the drug release microsphere is freely distributed, does not press and does not damage tissues, fully contacts with bone marrow fluid, guarantees the global uniform dispersion of drugs, locally releases drugs for a long time, maintains the effective drug concentration in the bone marrow cavity, has remarkable treatment effect, and rarely enters the whole body circulation, greatly reduces the side effects of drugs on the whole body, is minimally invasively implanted, is simple to operate, has small trauma, is fast in postoperative recovery, reduces the treatment cost and physical burden of patients, is preferably made of a degradable medical biocompatible material, has no immune rejection, can be synchronously degraded and has no residue, does not need secondary surgery, and is high in clinical safety. The drug release microsphere can be flexibly designed in specification, drug type and loading mode, is wide in clinical adaptability, can be used alone or in combination with other devices, and is rich in application scenarios.

Description

Technical Field

[0001] This invention relates to the field of medical device technology, and more particularly to a bone marrow cavity targeted drug delivery microsphere. Background Technology

[0002] The bone marrow cavity is the core microenvironment for hematopoiesis in the human body. Leukemia and other abnormal proliferative diseases of the bone marrow cavity require precise local drug action to achieve ideal therapeutic effects. Traditional treatments primarily involve systemic intravenous administration. However, the drug concentration drops significantly when it reaches the bone marrow cavity via blood circulation, making it difficult to achieve an effective therapeutic concentration. Furthermore, the widespread distribution of drugs can damage normal hematopoietic stem cells and systemic organs, leading to serious side effects such as bone marrow suppression, anemia, and organ dysfunction. Patients with low tolerance often find these treatments unacceptable.

[0003] Existing local drug delivery devices are mostly rigid, non-spherical structures, resulting in poor adaptability, difficult interventional implantation, and a tendency to compress hematopoietic tissue and obstruct bone marrow fluid circulation. Some devices are non-degradable, requiring a second surgery for removal after implantation, increasing patient trauma and treatment costs. Therefore, the development of a structurally adaptable, minimally invasive, locally effective, and long-acting intraosseous targeted drug delivery microsphere has become an urgent need in this field. Summary of the Invention

[0004] Purpose of the invention: The purpose of this invention is to overcome the shortcomings of the prior art and provide a bone marrow cavity targeted drug delivery microsphere to solve the problems in the treatment of traditional bone marrow cavity diseases. Most existing local drug delivery devices are rigid non-spherical structures with poor adaptability, difficult interventional implantation, and easy to compress hematopoietic tissue and hinder bone marrow fluid circulation. Some devices are non-degradable structures, requiring a second surgery to remove them after implantation, which increases patient trauma and treatment costs.

[0005] Technical solution: The invented intraosseous cavity targeted drug delivery microspheres are spherical in shape and contain drugs, and can be implanted into the intraosseous cavity.

[0006] The spherical structure is perfectly adapted to the irregular physiological microenvironment of the bone marrow cavity and the flow characteristics of bone marrow fluid. After implantation, it can be freely distributed in the bone marrow cavity without the risk of physical space occupation and compression, without damaging normal hematopoietic tissue, and can achieve maximum contact area with bone marrow fluid, ensuring that the drug can be quickly integrated into the bone marrow fluid after sustained release. Relying on the natural circulation of bone marrow fluid, the drug can be evenly diffused throughout the entire area and maintain a stable local treatment concentration.

[0007] The microspheres contain drugs, which are loaded onto the surface and / or interior of the spherical structure. After implantation, the drugs are released slowly and for a long time, avoiding the problems of sudden drug release and rapid metabolism caused by direct injection. The drugs are released locally in the bone marrow cavity and rarely enter the systemic blood circulation, which reduces systemic toxicity from the source and is suitable for patients of all ages.

[0008] Microspheres can be implanted into the bone marrow cavity, making them suitable for minimally invasive clinical interventional procedures. They do not require open surgery, are easy to operate, have minimal trauma, and allow for rapid postoperative recovery. They can be completed on an outpatient basis, reducing treatment costs and physical burden for patients.

[0009] Furthermore, the drug-releasing microspheres have a closed hollow spherical structure, which reduces the overall density and is more suitable for the flow characteristics of bone marrow fluid, achieving drug coverage of the bone marrow cavity without dead zones; at the same time, it prevents bone marrow fluid from entering the interior, prevents the drug release rate from getting out of control, and ensures sustained-release stability.

[0010] Furthermore, the drug-releasing microspheres are prepared using medical biocompatible materials, preferably medical biodegradable polymers such as polylactic acid (PLLA), polycaprolactone (PCL), and polylactic-glycolic acid copolymer (PLGA). These biodegradable materials exhibit excellent biocompatibility, do not cause immune rejection, and degrade simultaneously with the sustained release of the drug. The degradation products are carbon dioxide and water, which are metabolizable by the human body, eliminating the need for secondary surgery and avoiding foreign body irritation and secondary trauma.

[0011] Furthermore, the drug is loaded onto the outer surface of the microspheres to form a drug-eluting coating. The coating is a mixture of the drug and a medical biocompatible adhesive to ensure the adhesion of the coating and prevent it from falling off. The drug comes into direct contact with the bone marrow fluid, achieving rapid onset of action and uniform sustained release.

[0012] Furthermore, the degradation rate of the microspheres matches the sustained-release rate of the drug, and the microspheres are completely degraded after the drug is released, leaving no residue, thus improving the safety of clinical treatment.

[0013] Furthermore, the microspheres can be designed in different sizes, such as adult and children's sizes, to suit the physiological size of the medullary cavity of different populations, ensuring convenient implantation and uniform drug distribution.

[0014] Beneficial effects: 1. The spherical structure adapts to the microenvironment of the bone marrow cavity, allowing for free distribution after implantation without compression or tissue damage, and ensuring full contact with bone marrow fluid to guarantee uniform diffusion of the drug throughout the entire area; 2. Locally administered long-acting sustained-release drugs maintain effective drug concentration in the bone marrow cavity, resulting in significant therapeutic effects, with very little entering the systemic circulation, greatly reducing systemic drug side effects; 3. Minimally invasive interventional implantation is simple to operate, causes little trauma, and allows for rapid postoperative recovery, reducing treatment costs and physical burden for patients; 4. It uses biodegradable medical biocompatible materials, which do not cause immune rejection, can degrade simultaneously without residue, do not require secondary surgery, and have high clinical safety; 5. It allows for flexible design of specifications, drug types, and loading methods, has broad clinical applicability, and can be used alone or in combination with other devices, making it suitable for a wide range of applications. Attached Figure Description

[0015] Figure 1 This is a schematic diagram of the overall structure of the present invention. Detailed Implementation

[0016] To make the technical solution of the present invention clearer, the present invention will be further described in detail below with reference to the accompanying drawings and specific embodiments.

[0017] Microsphere preparation: PLLA and PCL are mixed and dried at a mass ratio of 7:3, heated to 180℃ to melt, and a closed hollow spherical blank is prepared by using a special mold. The outer diameter is 1.5~2mm and the wall thickness is 200~300μm. The microsphere matrix is ​​obtained by cooling and shaping. The microsphere matrix was ultrasonically cleaned with 75% medical ethanol for 15-20 minutes and vacuum dried for 2 hours. Then, it was hydrophilically modified with methoxy polyethylene glycol to obtain pretreated microspheres. Rapamycin and medical-grade polyethylene glycol adhesive were mixed at a ratio of 1:2.5 to prepare a drug coating solution of 200-300 μg / mL. The pretreated microspheres were immersed and removed at a pulling speed of 1-1.5 mm / s, and then vacuum dried and cured to obtain adult-grade drug-release microspheres.

[0018] Microsphere characteristics: Closed-loop hollow spherical structure containing rapamycin, suitable for implantation into the adult bone marrow cavity; PLLA / PCL biodegradable material with a degradation cycle of 9-12 months, matching the sustained-release rate of rapamycin, providing uniform low-dose sustained release with no residue after degradation; surface hydrophilic modification ensures good compatibility with bone marrow fluid and allows for free distribution.

[0019] Clinical Application: One adult patient with acute myeloid leukemia underwent CT-guided transiliac bone intervention with 10 microspheres. The microspheres freely distributed and released rapamycin, which diffused throughout the bone marrow cavity via bone marrow fluid. One month post-procedure, the patient's leukemia-related symptoms improved, and blood counts returned to normal. Three months post-procedure, bone marrow biopsy showed zero leukemia cells, MRD was negative, and blood counts returned to normal. Nine to twelve months post-procedure, the microspheres completely degraded, bone marrow hematopoietic function recovered, and no systemic side effects were observed, achieving clinical remission.

[0020] Example 2 Preparation and application of intraosseous targeted drug delivery microspheres for children Microsphere preparation: After drying PLGA, it is heated to 170℃ to melt, and a closed hollow spherical preform is prepared by mold with an outer diameter of 1~1.2mm and a sphere wall thickness of 200μm. After cooling, the microsphere matrix is ​​obtained. The microsphere matrix was ultrasonically cleaned with 75% medical ethanol for 15 minutes and vacuum dried for 2 hours. Then, it was hydrophilically modified with chitosan to obtain pretreated microspheres. Rapamycin and chitosan binder were mixed at a ratio of 1:2 to prepare a 200 μg / mL drug coating solution. The pretreated microspheres were dip-coated at a pulling speed of 1 mm / s and vacuum dried to obtain pediatric drug-release microspheres.

[0021] Microsphere properties The sealed, hollow spherical structure contains rapamycin and can be implanted into the pediatric bone marrow cavity. It is made of PLGA, a biodegradable material with a degradation cycle of 9 months, which matches the drug's sustained-release rate. The size is adapted to the pediatric bone marrow cavity, with no risk of compression and excellent biocompatibility.

[0022] Clinical application One pediatric patient with acute lymphoblastic leukemia underwent ultrasound-guided transsternal implantation of six microspheres. The drug was released gradually and diffused with the bone marrow fluid. Two months post-operation, the patient's hepatosplenomegaly subsided, and the immature cell count was 0. Nine months post-operation, the microspheres completely degraded, and bone marrow aspiration and MRD tests were both negative. Hematopoietic function recovered, and the patient experienced no adverse symptoms.

[0023] Example 3 Closed-loop therapy using microspheres in combination with circulatory pathway interception devices One adult patient with chronic myeloid leukemia underwent DSA-guided implantation of an inferior vena cava and thoracic duct stent to intercept abnormal cells in the peripheral blood and lymphatic circulation. Subsequently, eight adult-sized microspheres (as described in Example 1) were implanted via iliac bone intervention. The microspheres eradicated the primary lesion in the bone marrow cavity, while the stents intercepted metastatic cells, forming a closed-loop treatment. Six months post-procedure, no abnormal leukemia cells were found in the bone marrow cavity or peripheral circulation, and hematopoietic function recovered. Twelve months post-procedure, both the microspheres and stents degraded, and the patient achieved disease-free survival.

[0024] Industrial applicability The microspheres of this invention have a simple structure and are prepared using conventional processes in the field, such as melt molding, surface modification, and drug coating. They can be mass-produced using standardized molds, with easy control over the pass rate and low cost. The specifications, drug types, and preparation materials can be flexibly adjusted according to clinical needs, making them widely applicable in clinical practice. They solve the core pain points in the treatment of intramedullary diseases and have extremely high industrial production and clinical promotion value.

[0025] The drug-releasing microsphere 1 has a spherical structure with a drug-eluting coating covering its entire outer surface, which is adapted to the microenvironment of the bone marrow cavity and allows for full contact with the bone marrow fluid.

[0026] The drug-releasing microsphere 1 is a closed hollow spherical structure, consisting of a spherical structure, a hollow inner cavity, and a drug elution coating. The hollow structure reduces the density, and the coating enables sustained drug release.

[0027] After multiple drug-releasing microspheres are implanted into the bone marrow cavity, they are freely distributed in the bone marrow fluid, and the drug is absorbed into the bone marrow fluid and naturally circulates and diffuses.

[0028] The drug-release microsphere 1 is implanted into the bone marrow cavity to achieve primary lesion treatment, while the inferior vena cava intercepting stent 7 and the thoracic duct intercepting stent 8 are implanted into the corresponding pathways to achieve peripheral transfer interception, forming a closed-loop treatment.

[0029] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are specific and detailed, they should not be construed as limiting the scope of the present invention. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these modifications and improvements all fall within the scope of protection of the present invention. Therefore, the scope of protection of this patent should be determined by the appended claims.

Claims

1. A bone marrow cavity targeted drug delivery microsphere, characterized in that, The drug-releasing microspheres are spherical and contain drugs, and can be implanted into the bone marrow cavity.

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